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Astrocytic complexity distinguishes the human brain
Abstract
One of the most distinguishing features of the adult human brain is the complexity and diversity of its cortical astrocytes. Human protoplasmic astrocytes manifest a threefold larger diameter and have tenfold more primary processes than those of rodents. In all mammals, protoplasmic astrocytes are organized into spatially non-overlapping domains that encompass both neurons and vasculature. Yet unique to humans and primates are additional populations of layer 1 interlaminar astrocytes that extend long (millimeter) fibers, and layer 5-6 polarized astrocytes that also project distinctive long processes. We propose that human cortical evolution has been accompanied by increasing complexity in the form and function of astrocytes, which reflects an expansion of their functional roles in synaptic modulation and cortical circuitry.
... Studies revealed intrinsic differences between human astrocytes and those of lower mammals 30,31 , including anatomically defined subclasses of human astrocytes that are absent in rodents 29 . Besides the predominant protoplasmic astrocytes, at least three additional major morphological subclasses of GFAP + astrocytes have been identified in the adult human temporal lobe, including interlaminar astrocytes, a, Differentiation protocol schematic. ...
... Therefore, our organoid model provides an opportunity to study human astrocyte function in neurodevelopment and neurological diseases. Human astrocytic complexity correlates with the increased functional competence of the adult human brain 29,31 . In the human brain, astrocytes display a remarkable morphological diversity according to cortical layers and form anatomically defined subclasses 29,31 . ...
... Human astrocytic complexity correlates with the increased functional competence of the adult human brain 29,31 . In the human brain, astrocytes display a remarkable morphological diversity according to cortical layers and form anatomically defined subclasses 29,31 . Although neonatal engraftment of human glial progenitor cells has allowed the progressive expansion of human glial cells in the host brain [43][44][45] , to the best of our knowledge, it is still limited in fully reproducing the morphological complexity observed in the human brain. ...
Astrocytes, the most abundant glial cell type in the brain, are underrepresented in traditional cortical organoid models due to the delayed onset of cortical gliogenesis. Here we introduce a new glia-enriched cortical organoid model that exhibits accelerated astrogliogenesis. We demonstrated that induction of a gliogenic switch in a subset of progenitors enabled the rapid derivation of astroglial cells, which account for 25–31% of the cell population within 8–10 weeks of differentiation. Intracerebral transplantation of these organoids reliably generated a diverse repertoire of cortical neurons and anatomical subclasses of human astrocytes. Spatial transcriptome profiling identified layer-specific expression patterns among distinct subclasses of astrocytes within organoid transplants. Using an in vivo acute neuroinflammation model, we identified a subpopulation of astrocytes that rapidly activates pro-inflammatory pathways upon cytokine stimulation. Additionally, we demonstrated that CD38 signaling has a crucial role in mediating metabolic and mitochondrial stress in reactive astrocytes. This model provides a robust platform for investigating human astrocyte function.
... For example, transcriptional comparisons between human and rodent have revealed greater differences in glial gene expression signatures compared with neuronal-associated transcripts, suggesting that glial genes may be evolutionarily less conserved than neuronal genes. 11 Moreover, although mammalian astrocytes respond to glutamate and ATP by increasing intracellular calcium concentrations, human astrocytes support different calcium wave dynamics as compared with rodent astrocytes 12,13 which has the potential to affect subsequent release of glio-modulators. Pharmacological inhibition of the TGFb pathway partially prevents the synaptogenic effect of murine astrocyte-conditioned media on cortical neurons but abolishes the effect of human astrocyte-conditioned media, suggesting that human astrocytes may rely more heavily on TGFb signaling than their rodent counterparts. ...
... 14 Human astrocytes also display larger cellular diameters with more elaborated and compartmented processes compared with rodent astrocytes. 13 Indeed, although a rodent astrocyte domain can reportedly cover up to 120,000 synapses, a human astrocyte domain can cover up to 2 million synapses, suggesting greater processing complexity in the latter species. 13 These and other species-specific features highlight the likelihood of human astrocytes to differ from rodent astrocytes in their contributions to brain function and brain dysfunction. ...
... 13 Indeed, although a rodent astrocyte domain can reportedly cover up to 120,000 synapses, a human astrocyte domain can cover up to 2 million synapses, suggesting greater processing complexity in the latter species. 13 These and other species-specific features highlight the likelihood of human astrocytes to differ from rodent astrocytes in their contributions to brain function and brain dysfunction. Human astrocytes thus have important applications in studies of basic brain function, disease modeling and drug discovery. ...
Emerging evidence of species divergent features of astrocytes coupled with the relative inaccessibility of human brain tissue underscore the utility of human pluripotent stem cell (hPSC) technologies for the generation and study of human astrocytes. However, existing approaches for hPSC-astrocyte generation are typically lengthy or require intermediate purification steps. Here, we establish a rapid and highly scalable method for generating functional human induced astrocytes (hiAs). These hiAs express canonical astrocyte markers, respond to pro-inflammatory stimuli, exhibit ATP-induced calcium transients and support neuronal network development. Moreover, single-cell transcriptomic analyses reveal the generation of highly reproducible cell populations across individual donors, mostly resembling human fetal astrocytes. Finally, hiAs generated from a trisomy 21 disease model identify expected alterations in cell-cell adhesion and synaptic signaling, supporting their utility for disease modeling applications. Thus, hiAs provide a valuable and practical resource for the study of basic human astrocyte function and dysfunction in disease.
... The morphology and functionality of neuroglial cells were established in the 19th and early 20th century [13][14][15]. In addition, analysis of human evolution during the early 21st century revealed the role of neuroglia in the formation of the human intellect [16,17]. Likewise, the involvement of neuroglia in synaptic regulation and plasticity has been demonstrated, generating transient and even lasting changes in the force that can occur in a synapse [18,19]. ...
... Likewise, the involvement of neuroglia in synaptic regulation and plasticity has been demonstrated, generating transient and even lasting changes in the force that can occur in a synapse [18,19]. At the synapse, astrocytes are involved in formation of the human intellect [16,17]. Likewise, the involvement of neuroglia in synaptic regulation and plasticity has been demonstrated, generating transient and even lasting changes in the force that can occur in a synapse [18,19]. ...
... Moreover, astrocytes are territorial cells with processes controlling only a few overlaps between neighboring astrocytes [37], which are interconnected into functional networks [16,35]. It has been demonstrated that astrocyte cells maintain contact with up to 2,000,000 synapses [17,29] and this interaction depends on changes in neuronal activity. Furthermore, these astrocytes offer energy to neurons via lactate shuttle [38,39] and modulate Ca 2+ variations [40] (Figure 2). ...
In the central nervous system (CNS) there are a greater number of glial cells than neurons (between five and ten times more). Furthermore, they have a greater number of functions (more than eight functions). Glia comprises different types of cells, those of neural origin (astrocytes, radial glia, and oligodendroglia) and differentiated blood monocytes (microglia). During ontogeny, neurons develop earlier (at fetal day 15 in the rat) and astrocytes develop later (at fetal day 21 in the rat), which could indicate their important and crucial role in the CNS. Analysis of the phylogeny reveals that reptiles have a lower number of astrocytes compared to neurons and in humans this is reversed, as there have a greater number of astrocytes compared to neurons. These data perhaps imply that astrocytes are important and special cells, involved in many vital functions, including memory, and learning processes. In addition, astrocytes are involved in different mechanisms that protect the CNS through the production of antioxidant and anti-inflammatory proteins and they clean the extracellular environment and help neurons to communicate correctly with each other. The production of inflammatory mediators is important to prevent changes in brain homeostasis. On the contrary, excessive, or continued production appears as a characteristic element in many diseases, such as Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and in neurodevelopmental diseases, such as bipolar disorder, schizophrenia, and autism. Furthermore, different drugs and techniques have been developed to reverse oxidative stress and/or excess of inflammation that occurs in many CNS diseases, but much remains to be investigated. This review attempts to highlight the functional relevance of astrocytes in normal and neuropathological conditions by showing the molecular and cellular mechanisms of their role in the CNS.
... An astrocyte domain defines a contiguous cohort of synapses that interacts exclusively with a single astrocyte. Synapses within a particular territory are thereby linked via a shared astrocyte partner, independent of a neuronal networking (Oberheim et al. 2006). Figure 8.3 shows an outline of an astrocyte domain organization. ...
... Astrocyte (Ac x ) is interconnected with Ac y via gap junctions (g.j.). roughly two million synapses in the cerebral cortex (Oberheim et al. 2006). Astrocytic receptors are mainly located on the endfeet of the processes. ...
The present study deals with elementary reflection mechanisms in the
brain focusing on glial-neuronal synaptic units, astrocyte domain organization
and the astrocytic syncytium. These reflection mechanisms
are formally based on a novel relationship, called proemial. The brain
may be composed of many ontological realms consisting of myriads of
glial-neuronal synaptic units with their volitive-intentional and cognitiveperceptive
networks embodying many subjective realities based on Ego-
Thou reflections. Basically, these structures and functions of our brain
enable it to prelude or reflect all possible interactions with the environment.
Here, we may deal with reflection mechanisms that determine
consciousness, but do not reach awareness.
... These results not only further underline the crucial role of GDH in cerebral glutamate homeostasis but may also suggest that the combination of high GS and GDH activity of the human brain jointly acts as a metabolic defense against harmful elevations in extracellular glutamate levels. The great size and morphological complexity of astrocytes is a hallmark of the human brain (Oberheim et al., 2006(Oberheim et al., , 2009 and future efforts should be devoted to further elucidating the metabolic function of, and collaboration between, human neurons and astrocytes. ...
... When the Na + /K + -ATPase activity of astrocytes (MacAulay, 2020), which is crucial to buffer synaptic K + , is taken into account, it has been argued that astrocytes may be as energetically expensive as neurons (Barros, 2022). Finally, when the size and complexity of human astrocytes are considered (Oberheim et al., 2006), the metabolic contribution of astrocytes in the human brain may have been severely underestimated (Dienel & Rothman, 2020). Collectively, these notions suggest that altered astrocyte function and metabolism may significantly contribute to pathological changes in brain metabolism. ...
Since it was first generally accepted that the two amino acids glutamate and GABA act as principal neurotransmitters, several landmark discoveries relating to this function have been uncovered. Synaptic homeostasis of these two transmitters involves several cell types working in close collaboration and is facilitated by specialized cellular processes. Notably, glutamate and GABA are extensively recycled between neurons and astrocytes in a process known as the glutamate/GABA‐glutamine cycle, which is essential to maintain synaptic transmission. The glutamate/GABA‐glutamine cycle is intimately coupled to cellular energy metabolism and relies on the metabolic function of both neurons and astrocytes. Importantly, astrocytes display unique metabolic features allowing extensive metabolite release, hereby providing metabolic support for neurons. Furthermore, astrocytes undergo complex metabolic adaptations in response to injury and pathology, which may greatly affect the glutamate/GABA‐glutamine cycle and synaptic transmission during disease. In this Milestone Review we outline major discoveries in relation to synaptic balancing of glutamate and GABA signaling, including cellular uptake, metabolism, and recycling. We provide a special focus on how astrocyte function and metabolism contribute to sustain neuronal transmission through metabolite transfer. Recent advances on cellular glutamate and GABA homeostasis are reviewed in the context of brain pathology, including glutamate toxicity and neurodegeneration. Finally, we consider how pathological astrocyte metabolism may serve as a potential target of metabolic intervention. Integrating the multitude of fine‐tuned cellular processes supporting neurotransmitter recycling, will aid the next generation of major discoveries on brain glutamate and GABA homeostasis. image
... On the cellular level, the mediation process in the brain can be explained as a glial-neuronal interaction. This means that a spatio-temporal boundary-setting function is attributed to the glial cells (astrocytes, oligodendrocytes), such that the glial cells determine the grouping of neurons into functional units [15] [16]. If we suppose that "chimeric" (truncated) receptors are generated and expressed on the surface of glial cells, these receptors cannot be occupied by their cognate ligands resulting in glia that lose their inhibitory-rejecting function with respect to the information processing within neuronal networks. ...
... I have hypothesized that the glial networks have a boundary setting function in their interactions with the neuronal networks [15] [28]. Various experimental indications support the hypothesis that the glial-neuronal networks are organized in the form of domains as self-organizing units [16] [29]. According to Smolin [30] the setting of boundaries is an absolute prerequisite for a description of the universe. ...
... However, these studies also come with significant drawbacks. The most apparent limitation of animal models is the differences in neurobiology between model species and humans (203)(204)(205)(206). Indeed, rodents, the primary models in this field, lack the full complement of glial complexity seen in humans, and certain vascular and immunological components are also absent (207). Moreover, their short lifespans limit the development of progressive diseases (208), potentially leading to the incomplete development of molecular and cellular pathological hallmarks in brain-associated immune niches. ...
Historically, the central nervous system (CNS) was regarded as ‘immune-privileged’, possessing its own distinct immune cell population. This immune privilege was thought to be established by a tight blood-brain barrier (BBB) and blood-cerebrospinal-fluid barrier (BCSFB), which prevented the crossing of peripheral immune cells and their secreted factors into the CNS parenchyma. However, recent studies have revealed the presence of peripheral immune cells in proximity to various brain-border niches such as the choroid plexus, cranial bone marrow (CBM), meninges, and perivascular spaces. Furthermore, emerging evidence suggests that peripheral immune cells may be able to infiltrate the brain through these sites and play significant roles in driving neuronal cell death and pathology progression in neurodegenerative disease. Thus, in this review, we explore how the brain-border immune niches may contribute to the pathogenesis of neurodegenerative disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and multiple sclerosis (MS). We then discuss several emerging options for harnessing the neuroimmune potential of these niches to improve the prognosis and treatment of these debilitative disorders using novel insights from recent studies.
... Dacinostat (LAQ824) has been shown to anticancer agent against growth of glioblastoma because ability to blood brain barrier(BBB) permeability [56]. Dacinostat (LAQ824) helps in the promotion of apoptosis in glioblastoma via increasing accumulation of acetylation on histones, inducing cell cycle arrest, and upregulating P21 [57,58]. ...
Epigenetic abnormality is one of the hallmarks of glioblastoma cancer cells. Histone deacetylase (HDAC) modification has a crucial role in epigenetic abnormality, which results in the initiation and progression of glioblastoma cancer cells. The selective HDAC inhibitors are well-known epigenetic regulators and promising anti-cancer agents that target specific HDAC enzymes and inhibit the proliferation of many cancer cells. Selective HDAC inhibitors isoform provides a high efficacy as chemotherapy in inhibiting cancer confirmation compared to non-selective HDAC inhibitors. Additionally, selective HDAC inhibitors suppress Class -I HDAC1, HDAC2, HDAC3, and HDAC11. HDAC class I inhibitors induce apoptosis, differentiation, autophagic death cells, and reactive oxygen species (ROS)- induced cell death, inhibit cell migration, invasion, and angiogenesis in cancer cells, while the normal cells showed more resistance to HDAC class I inhibitors. Mocetinostat (MGCD0103), a benzamide histone deacetylase, is a potent anti-cancer therapy for the treatment of several cancer cell lines and induction of autophagy. It has been approved by The Food and Drug Administration (FDA) for the treatment of Hodgkin lymphoma (HL) cell lines. MGCD0103 is a synthesized and selective HDAC inhibitor that has vigorous inhibitory activity against Class-I and IV HDAC. MGCD0103 is well tolerated and has favorable pharmacokinetic properties, pharmacodynamic profile, and fast absorption within 1 hour after oral administration, long elimination half-life, and sustained HDAC inhibition. Therefore, MGCD0103 is expected to be a promising anti-cancer drug for treating several types of human cancer cells. Keywords: MGCD0103; Apoptosis; Differentiation; Gliblastoma; HDAC; inhibitors.
... Among glial cells, "starlike" astrocytes are the cells whose relative number, size, number of ramified processes and volume increased with phylogeny and brain complexity (Nedergaard et al., 2003). Depending on the different regions, astrocytes represent 20−40% of all brain cells (Herculano-Houzel, 2014) and show different morphology, ranging from protoplasmic to spherical shape (Emsley and Macklis, 2006;Oberheim et al., 2006). In the brain, each astrocyte occupies a specific territory, with less of 5% of overlap with neighboring astrocytes (Ogata and Kosaka, 2002). ...
Astrocytes are highly plastic cells whose activity is essential to maintain the cerebral homeostasis, regulating synaptogenesis and synaptic transmission, vascular and metabolic functions, ions, neuro- and gliotransmitters concentrations. In pathological conditions, astrocytes may undergo transient or long-lasting molecular and functional changes that contribute to disease resolution or exacerbation. In recent years, many studies demonstrated that non-neoplastic astrocytes are key cells of the tumor microenvironment that contribute to the pathogenesis of glioblastoma, the most common primary malignant brain tumor and of secondary metastatic brain tumors. This Mini Review covers the recent development of research on non-neoplastic astrocytes as tumor-modulators. Their double-edged capability to promote cancer progression or to represent potential tools to counteract brain tumors will be discussed.
... The size, arborization, and proportion of glial cells to neurons in mice differ substantially from those in primates (Geirsdottir et al., 2020;Taber & Hurley, 2008). For instance, NHP astrocytes develop more abundant processes compared to those in mice, resembling the astrocytes found in humans (Falcone et al., 2019;Matyash & Kettenmann, 2010;Oberheim et al., 2006;Rash et al., 2019). Additionally, astrocytes contribute to the blood-brain barrier (BBB) and regulate the exchange of materials between capillaries and cerebral parenchyma (Knox et al., 2022;Xu et al., 2013). ...
Neurodegenerative diseases (NDs) are a group of debilitating neurological disorders that primarily affect elderly populations and include Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). Currently, there are no therapies available that can delay, stop, or reverse the pathological progression of NDs in clinical settings. As the population ages, NDs are imposing a huge burden on public health systems and affected families. Animal models are important tools for preclinical investigations to understand disease pathogenesis and test potential treatments. While numerous rodent models of NDs have been developed to enhance our understanding of disease mechanisms, the limited success of translating findings from animal models to clinical practice suggests that there is still a need to bridge this translation gap. Old World non-human primates (NHPs), such as rhesus, cynomolgus, and vervet monkeys, are phylogenetically, physiologically, biochemically, and behaviorally most relevant to humans. This is particularly evident in the similarity of the structure and function of their central nervous systems, rendering such species uniquely valuable for neuroscience research. Recently, the development of several genetically modified NHP models of NDs has successfully recapitulated key pathologies and revealed novel mechanisms. This review focuses on the efficacy of NHPs in modeling NDs and the novel pathological insights gained, as well as the challenges associated with the generation of such models and the complexities involved in their subsequent analysis.
... By using the fluorescent dye iontophoresis technique, Bushong et al. showed that adjacent astrocytes in the hippocampal CA1 region possess independent spatial domains with minimal overlap between their branches [4]. From then on, the concept that astrocytes in the adult brain have non-overlapping territory has become widely accepted [5][6][7][8][9], which has been further strengthened by studies on human and drosophila brains [10,11]. However, it is noteworthy that astrocytes in the ferret visual cortex share half of their territory with other astrocytes [12], and the processes of the interdigitation of adjacent astrocytes were also reported in the colliculus in a study using a Brainbow transgenic mice line [13]. ...
Astrocytes are morphologically intricate cells and actively modulate the function of the brain. Through numerous fine processes, astrocytes come into contact with neurons, blood vessels, and other glia cells. Emerging evidence has shown that astrocytes exhibit brain regional diversity in their morphology, transcriptome, calcium signaling, and functions. However, little is known about the brain regional heterogeneity of astrocyte–astrocyte structural interaction. So far, the visualization and characterization of the morphological features of adjacent astrocytes have been difficult, and as a result, it is still well-accepted that astrocytes in the adult brain share non-overlapped territory. In contrast, employing an approach that combines viral labeling with dual-fluorescent dyes iontophoresis under brightfield and imaging using confocal microscopy allows for the efficient and specific labeling of adjacent astrocytes, enabling a comprehensive visualization of their fine processes and the degree of their territorial overlap. Our study in the hypothalamic regions of the brain revealed a marked spatial overlap among adjacent astrocytes, which differs from the conventional understanding based on more extensively studied regions, like the hippocampus. Additionally, we revealed the heterogeneity of the astrocyte–neuron ratio across brain regions and conducted an assessment of the photostability and labeling efficiency of fluorescent dyes used for labeling adjacent astrocytes. Our study provides new insights for studying the morphological heterogeneity of astrocytes across the central nervous system.
... The greater complexity of ILAs in humans is thought to have a potential role in long-distance intra-cortical communication, coordination, and neuronal support (Oberheim et al., 2006;Oberheim et al., 2009) since the disruption of ILA intralaminar processes has been reported in pathologies such as Alzheimer's disease (Colombo et al., 2002) and Down's syndrome (Colombo et al., 2005). ...
Glia have emerged as important architects of central nervous system (CNS) development and maintenance. While traditionally glial contributions to CNS development and maintenance have been studied independently, there is growing evidence that either suggests or documents that glia may act in coordinated manners to effect developmental patterning and homeostatic functions in the CNS. In this review, we focus on astrocytes, the most abundant glia in the CNS, and microglia, the earliest glia to colonize the CNS highlighting research that documents either suggestive or established coordinated actions by these glial cells in various CNS processes including cell and/or debris clearance, neuronal survival and morphogenesis, synaptic maturation, and circuit function, angio−/vasculogenesis, myelination, and neurotransmission. Some molecular mechanisms underlying these processes that have been identified are also described. Throughout, we categorize the available evidence as either suggestive or established interactions between microglia and astrocytes in the regulation of the respective process and raise possible avenues for further research. We conclude indicating that a better understanding of coordinated astrocyte‐microglial interactions in the developing and mature brain holds promise for developing effective therapies for brain pathologies where these processes are perturbed.
... From the stellate cellular bodies of these fibrous AS emerge long, thin, and straight processes ( Figure 1) [2]. The protoplasmic AS which reside in the grey matter of the CNS have fewer glial filaments [7] and ovoid or irregular cellular bodies with numerous, short, dichotomized processes [9,10]. Bergmann glial cells or epithelial glial cells are AS with long processes located in the granular layers of the cerebellar cortex [4]. ...
Astrocytes (AS) are the most abundant glial cells in the central nervous system (CNS). They have various morphologies and numerous (50-60) branching prolongations, with roles in the maintenance of the CNS function and homeostasis. AS in the optic nerve head (ONH) have specific distribution and function and are involved in the pathogenesis of glaucoma and other neural diseases, modify their morphologies, location, immune phenotype, and ultrastructure, thus being the key players in the active remodeling processes of the ONH.
... Astrocytes are also involved in metabolic support, providing neurons with essential nutrients and regulating blood flow (Sofroniew & Vinters, 2010). Their complexity even distinguishes the human brain from other species (Oberheim et al., 2006). Moreover, astrocytes have been found to play a role in pathological conditions like epilepsy, characterized by abnormal brain waves (Fields et al., 2014). ...
Astrocytes, once relegated to the role of mere 'support cells' in the central nervous system, are emerging as key players in neural conduction and overall brain function. This article aims to elucidate the multifaceted roles of astrocytes, exploring why they have been historically overshadowed by neurons and how they contribute to the complexity of brain wave patterns. Through a series of computational simulations and a comprehensive review of existing literature, we demonstrate that astrocytes are not just passive bystanders but active participants in neural signaling. The article also discusses the implications of astrocyte function for cognitive abilities like learning, memory, and attention, as well as their role in pathological conditions like epilepsy. With 15 pertinent references, this article serves as a comprehensive review that challenges the neuron-centric view of brain function and calls for a reevaluation of the roles of astrocytes in neuroscience.
... This cytoplasmic Ca 2+ is released by its channels on the endoplasmic reticule after the Glu stimulation through the G-protein/phosphatidylinositoltriphosphate/inositol-triphosphate [94] pathway. As already highlighted [7,95], the relevance of these depolarizations is based on the astrocyte's extreme capacity of building interactions with up to 100,000 [96] or even 2,000,000 [97,98] synapses. So, in the light of such a rapid glance into Ca 2+ homeostasis in the crosstalk between neural and glial transmitters, astrocytes cannot generate an action potential [99], but they are excitable towards several stimuli. ...
This work aimed at assessing Alzheimer’s disease (AD) pathogenesis through the investigation of the astrocytic role to transduce the load of amyloid-beta (Aβ) into neuronal death. The backbone of this review is focused on the deepening of the molecular pathways eliciting the activation of astrocytes crucial phenomena in the understanding of AD as an autoimmune pathology. The complex relations among astrocytes, Aβ and tau, together with the role played by the tripartite synapsis are discussed. A review of studies published from 1979 to 2023 on Scopus, PubMed and Google Scholar databases was conducted. The selected papers focused not only on the morphological and metabolic characteristics of astrocytes, but also on the latest notions about their multifunctional involvement in AD pathogenesis. Astrocytes participate in crucial pathways, including pruning and sprouting, by which the AD neurodegeneration evolves from an aggregopathy to neuroinflammation, loss of synapses and neuronal death. A1 astrocytes stimulate the production of pro-inflammatory molecules which have been correlated with the progression of AD cognitive impairment. Further research is needed to “hold back” the A1 polarization and, thus, to slow the worsening of the disease. AD clinical expression is the result of dysfunctional neuronal interactions, but this is only the end of a process involving a plurality of protagonists. One of these is the astrocyte, whose importance this work intends to put under the spotlight in the AD scenario, reflecting the multifaceted nature of this disease in the functional versatility of this glial population.
... For instance, it has been noted that increased astrocyte-to-neuron ratio, highly ramified (hence potentially able to create more connections) astrocytic morphology, and increased variety of astrocyte subtypes correlate with behavioral and cognitive complexity of organisms to a greater extent than an increase in neuronal complexityhuman cortical protoplasmic astrocytes present with a staggering 27-fold increase in volume, 2.55-fold increase in diameter, ten times more processes, over 20-fold increase in the number of interacting synapses, and over five times faster calcium waves compared to their rodent counterparts, while human neurons are only ≈2.5 times larger. [42,83] While neuronal connectivity and signaling were traditionally considered to be the foundation of the computational ability of the brain, it has been recently demonstrated mathematically that astrocytic networks are capable of reaching a comparable computational complexity, [84] and inclusion of "digital astrocytes" in a neural net machine learning algorithm was found to improve the model's computational performance. [85] Interestingly, the brain of the famous physicist Albert Einstein contained lower neuron-to-glia (nonneuronal cells including astrocytes) ratio in a brain area associated with mathematical performance, [86] and astrocytic processes in his brain were distinguished by a higher complexity compared to an average individual-although causal relationship between astrocytic morphologies and cognitive performance have been disputed. ...
Astrocytes are diverse brain cells that form large networks communicating via gap junctions and chemical transmitters. Despite recent advances, the functions of astrocytic networks in information processing in the brain are not fully understood. In culture, brain slices, and in vivo, astrocytes, and neurons grow in tight association, making it challenging to establish whether signals that spread within astrocytic networks communicate with neuronal groups at distant sites, or whether astrocytes solely respond to their local environments. A multi‐electrode array (MEA)‐based device called AstroMEA is designed to separate neuronal and astrocytic networks, thus allowing to study the transfer of chemical and/or electrical signals transmitted via astrocytic networks capable of changing neuronal electrical behavior. AstroMEA demonstrates that cortical astrocytic networks can induce a significant upregulation in the firing frequency of neurons in response to a theta‐burst charge‐balanced biphasic current stimulation (5 pulses of 100 Hz × 10 with 200 ms intervals, 2 s total duration) of a separate neuronal‐astrocytic group in the absence of direct neuronal contact. This result corroborates the view of astrocytic networks as a parallel mechanism of signal transmission in the brain that is separate from the neuronal connectome. Translationally, it highlights the importance of astrocytic network protection as a treatment target.
... This could bring insights into whether astrocytes respond by boosting endogenous signalling pathways, or by triggering new ones, generating insights into potential signalling pathways that can be exploited therapeutically. Another key aspect to take into consideration is that mouse and human astrocytes are morphologically, transcriptionally, and functionally different (Oberheim et al., 2006;Li et al., 2021). Using, for example, Frontiers in Cell and Developmental Biology frontiersin.org ...
Astrocytes are the major glial cell type in the central nervous system (CNS). Initially regarded as supportive cells, it is now recognized that this highly heterogeneous cell population is an indispensable modulator of brain development and function. Astrocytes secrete neuroactive molecules that regulate synapse formation and maturation. They also express hundreds of G protein-coupled receptors (GPCRs) that, once activated by neurotransmitters, trigger intracellular signalling pathways that can trigger the release of gliotransmitters which, in turn, modulate synaptic transmission and neuroplasticity. Considering this, it is not surprising that astrocytic dysfunction, leading to synaptic impairment, is consistently described as a factor in brain diseases, whether they emerge early or late in life due to genetic or environmental factors. Here, we provide an overview of the literature showing that activation of genetically engineered GPCRs, known as Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), to specifically modulate astrocyte activity partially mimics endogenous signalling pathways in astrocytes and improves neuronal function and behavior in normal animals and disease models. Therefore, we propose that expressing these genetically engineered GPCRs in astrocytes could be a promising strategy to explore (new) signalling pathways which can be used to manage brain disorders. The precise molecular, functional and behavioral effects of this type of manipulation, however, differ depending on the DREADD receptor used, targeted brain region and timing of the intervention, between healthy and disease conditions. This is likely a reflection of regional and disease/disease progression-associated astrocyte heterogeneity. Therefore, a thorough investigation of the effects of such astrocyte manipulation(s) must be conducted considering the specific cellular and molecular environment characteristic of each disease and disease stage before this has therapeutic applicability.
... Recent research in neuromorphic computing has started focusing on other cellular components in the brain that might contribute to cognition in addition to neuronal spiking behavior and synaptic plasticity. Specifically, this work explores the contribution of one such component -glial cells, in particular, the astrocytes (Oberheim et al. 2006). It has been observed that neurotransmitters released from a neuron can trigger diffusing Ca 2+ waves inside the cytoplasm Copyright © 2023, Association for the Advancement of Artificial Intelligence (www.aaai.org). ...
While neuromorphic computing architectures based on Spiking Neural Networks (SNNs) are increasingly gaining interest as a pathway toward bio-plausible machine learning, attention is still focused on computational units like the neuron and synapse. Shifting from this neuro-synaptic perspective, this paper attempts to explore the self-repair role of glial cells, in particular, astrocytes. The work investigates stronger correlations with astrocyte computational neuroscience models to develop macro-models with a higher degree of bio-fidelity that accurately captures the dynamic behavior of the self-repair process. Hardware-software co-design analysis reveals that bio-morphic astrocytic regulation has the potential to self-repair hardware realistic faults in neuromorphic hardware systems with significantly better accuracy and repair convergence for unsupervised learning tasks on the MNIST and F-MNIST datasets. Our implementation source code and trained models are available at https://github.com/NeuroCompLab-psu/Astromorphic_Self_Repair.
... Astrocytes are the most abundant glia cells in the CNS. Astrocytes maintain homeostasis of neuronal populations and are intimately involved in various neurological disorders 36,37 . AAV serotypes that can efficiently target astrocytes are of great interest to the academia and industry. ...
Viral tracers that enable efficient retrograde labeling of projection neurons are powerful vehicles for structural and functional dissections of the neural circuit and for the treatment of brain diseases. Currently, some recombinant adeno-associated viruses (rAAVs) based on capsid engineering are widely used for retrograde tracing, but display undesirable brain area selectivity due to inefficient retrograde transduction in certain neural connections. Here we developed an easily editable toolkit to produce high titer AAV11 and demonstrated that it exhibits potent and stringent retrograde labeling of projection neurons in adult male wild-type or Cre transgenic mice. AAV11 can function as a powerful retrograde viral tracer complementary to AAV2-retro in multiple neural connections. In combination with fiber photometry, AAV11 can be used to monitor neuronal activities in the functional network by retrograde delivering calcium-sensitive indicator under the control of a neuron-specific promoter or the Cre-lox system. Furthermore, we showed that GfaABC1D promoter embedding AAV11 is superior to AAV8 and AAV5 in astrocytic tropism in vivo, combined with bidirectional multi-vector axoastrocytic labeling, AAV11 can be used to study neuron-astrocyte connection. Finally, we showed that AAV11 allows for analyzing circuit connectivity difference in the brains of the Alzheimer’s disease and control mice. These properties make AAV11 a promising tool for mapping and manipulating neural circuits and for gene therapy of some neurological and neurodegenerative disorders.
... It is important to note that astrocytes are important for supporting and regulating the function of neurons, so any changes in their interactions could affect the overall functioning of the brain. Glial morphological and functional changes have been observed in human brain tissues from post-mortem or surgically resected patients who had a variety of brain disorders [110,111]. We presented the strong and weak effects of astrocytes (i.e., sM 2-sM 3 models) in the human brains of AD patients using clinical data. ...
Alzheimer's disease (AD) is a prominent, worldwide, age-related neurodegenerative disease that currently has no systemic treatment. Strong evidence suggests that permeable amyloid-beta peptide (Abeta) oligomers, astrogliosis and reactive astrocytosis cause neuronal damage in AD. A large amount of Abeta is secreted by astrocytes, which contributes to the total Abeta deposition in the brain. This suggests that astrocytes may also play a role in AD, leading to increased attention to their dynamics and associated mechanisms. Therefore, in the present study, we developed and evaluated novel stochastic models for Abeta growth using ADNI data to predict the effect of astrocytes on AD progression in a clinical trial. In the AD case, accurate prediction is required for a successful clinical treatment plan. Given that AD studies are observational in nature and involve routine patient visits, stochastic models provide a suitable framework for modelling AD. Using the approximate Bayesian computation (ABC) approach, the AD etiology may be modelled as a multi-state disease process. As a result, we use this approach to examine the weak and strong influence of astrocytes at multiple disease progression stages using ADNI data from the baseline to 2-year visits for AD patients whose ages ranged from 50 to 90 years. Based on ADNI data, we discovered that the strong astrocyte effect (i.e., a higher concentration of astrocytes as compared to Abeta) could help to lower or clear the growth of Abeta, which is a key to slowing down AD progression.
... Therefore, astrocytes are significantly involved in synapse formation, remodeling, and plasticity [17][18][19], which is partly due to their evolutionarily conserved intricate branched morphology-proven both in mice and humans- [20,21]. The perisynaptic astrocytic processes (PAPs) that establish physical contact with pre-and post-synaptic terminals and form tripartite synapses [22] can undergo both gross and fine-scale structural changes analogous to those seen in neurons during plasticity modulation [23][24][25][26]. ...
While neurons have traditionally been considered the primary players in information processing, the role of astrocytes in this mechanism has largely been overlooked due to experimental constraints. In this review, we propose that astrocytic ensembles are active working groups that contribute significantly to animal conduct and suggest that studying the maps of these ensembles in conjunction with neurons is crucial for a more comprehensive understanding of behavior. We also discuss available methods for studying astrocytes and argue that these ensembles, complementarily with neurons, code and integrate complex behaviors, potentially specializing in concrete functions.
... Astrocytes are a glial cell type essential to the proper functioning of the brain, contributing to neurogenesis, synaptogenesis [1], synaptic plasticity [2] and memory encoding [3]. Astrocytes can associate with many neurons and thereby thousands to millions of synapses [4][5][6], where they communicate with neurons bidirectionally [7]. Astrocytes can modulate neuronal function at the network level, where they are positioned to respond to neural network activity and impose a significant impact on that activity under both physiological and pathological conditions [8]. ...
Secreted amyloid precursor protein alpha (sAPPα), processed from a parent mammalian brain protein, amyloid precursor protein, can modulate learning and memory. Recently it has been shown to modulate the transcriptome and proteome of human neurons, including proteins with neurological functions. Here, we analysed whether the acute administration of sAPPα facilitated changes in the proteome and secretome of mouse primary astrocytes in culture. Astrocytes contribute to the neuronal processes of neurogenesis, synaptogenesis and synaptic plasticity. Cortical mouse astrocytes in culture were exposed to 1 nM sAPPα, and changes in both the whole-cell proteome (2 h) and the secretome (6 h) were identified with Sequential Window Acquisition of All Theoretical Fragment Ion Spectra–Mass Spectrometry (SWATH-MS). Differentially regulated proteins were identified in both the cellular proteome and secretome that are involved with neurologically related functions of the normal physiology of the brain and central nervous system. Groups of proteins have a relationship to APP and have roles in the modulation of cell morphology, vesicle dynamics and the myelin sheath. Some are related to pathways containing proteins whose genes have been previously implicated in Alzheimer’s disease (AD). The secretome is also enriched in proteins related to Insulin Growth Factor 2 (IGF2) signaling and the extracellular matrix (ECM). There is the promise that a more specific investigation of these proteins will help to understand the mechanisms of how sAPPα signaling affects memory formation.
... In conjunction with early synapse loss, astrocyte atrophy has been observed in neurodegenerative disease, including Parkinson's disease, where an analysis of dysregulated genetic expression is also mainly astrocytic in origin [128,129]. Astrocytic dysfunction is particularly impactful to the human brain, where astrocytes in the cortex are 27 times greater in volume and have 10 times as many terminal processes, estimated to contact up to 2 × 10 6 synapses compared with 1.2 × 10 5 in the rodent [130,131]. ...
Synucleins consist of three proteins exclusively expressed in vertebrates. α-Synuclein (αS) has been identified as the main proteinaceous aggregate in Lewy bodies, a pathological hallmark of many neurodegenerative diseases. Less is understood about β-synuclein (βS) and γ-synuclein (γS), although it is known βS can interact with αS in vivo to inhibit aggregation. Likewise, both γS and βS can inhibit αS’s propensity to aggregate in vitro. In the central nervous system, βS and αS, and to a lesser extent γS, are highly expressed in the neural presynaptic terminal, although they are not strictly located there, and emerging data have shown a more complex expression profile. Synapse loss and astrocyte atrophy are early aspects of degenerative diseases of the brain and correlate with disease progression. Synucleins appear to be involved in synaptic transmission, and astrocytes coordinate and organize synaptic function, with excess αS degraded by astrocytes and microglia adjacent to the synapse. βS and γS have also been observed in the astrocyte and may provide beneficial roles. The astrocytic responsibility for degradation of αS as well as emerging evidence on possible astrocytic functions of βS and γS, warrant closer inspection on astrocyte–synuclein interactions at the synapse.
Astrocytes in the cerebrum play important roles such as the regulation of synaptic functions, homeostasis, water transport, and the blood–brain barrier. It has been proposed that astrocytes in the cerebrum acquired diversity and developed functionally during evolution. Here, we show that like human astrocytes, ferret astrocytes in the cerebrum exhibit various morphological subtypes which mice do not have. We found that layer 1 of the ferret cerebrum contained not only protoplasmic astrocytes but also pial interlaminar astrocytes and subpial interlaminar astrocytes. Morphologically polarized astrocytes, which have a long unbranched process, were found in layer 6. Like human white matter, ferret white matter exhibited four subtypes of astrocytes. Furthermore, our quantification showed that ferret astrocytes had a larger territory size and a longer radius length than mouse astrocytes. Thus, our results indicate that, similar to the human cerebrum, the ferret cerebrum has a well‐developed diversity of astrocytes. Ferrets should be useful for investigating the molecular and cellular mechanisms leading to astrocyte diversity, the functions of each astrocyte subtype and the involvement of different astrocyte subtypes in various neurological diseases.
Extracellular vesicles (EVs) are secreted by all cells in the CNS, including neurons and astrocytes. EVs are lipid membrane enclosed particles loaded with various bioactive cargoes reflecting the dynamic activities of cells of origin. In contrast to neurons, the specific role of EVs released by astrocytes is less well understood, partly due to the difficulty in maintaining primary astrocyte cultures in a quiescent state. The aim of this study was to establish a human serum-free astrocyte culture system that maintains primary astrocytes in a quiescent state to study the morphology, function, and protein cargoes of astrocyte-derived EVs. Serum-free medium with G5 supplement and serum-supplemented medium with 2% FBS were compared for the culture of commercially available human primary fetal astrocytes. Serum-free astrocytes displayed morphologies similar to in vivo astrocytes, and surprisingly, higher levels of astrocyte markers compared to astrocytes chronically cultured in FBS. In contrast, astrocyte and inflammatory markers in serum-free astrocytes were upregulated 24 h after either acute 2% FBS or cytokine exposure, confirming their capacity to become reactive. Importantly, this suggests that distinct signaling pathways are involved in acute and chronic astrocyte reactivity. Despite having a similar morphology, chronically serum-cultured astrocyte-derived EVs (ADEVs) were smaller in size compared to serum-free ADEVs and could reactivate serum-free astrocytes. Proteomic analysis identified distinct protein datasets for both types of ADEVs with enrichment of complement and coagulation cascades for chronically serum-cultured astrocyte-derived EVs, offering insights into their roles in the CNS. Collectively, these results suggest that human primary astrocytes cultured in serum-free medium bear similarities with in vivo quiescent astrocytes and the addition of serum induces multiple morphological and transcriptional changes that are specific to human reactive astrocytes and their ADEVs. Thus, more emphasis should be made on using multiple structural, molecular, and functional parameters when evaluating ADEVs as biomarkers of astrocyte health.
Genomic profiling in postmortem brain from autistic individuals has consistently revealed convergent molecular changes. What drives these changes and how they relate to genetic susceptibility in this complex condition are not well understood. We performed deep single-nucleus RNA sequencing (snRNA-seq) to examine cell composition and transcriptomics, identifying dysregulation of cell type–specific gene regulatory networks (GRNs) in autism spectrum disorder (ASD), which we corroborated using single-nucleus assay for transposase-accessible chromatin with sequencing (snATAC-seq) and spatial transcriptomics. Transcriptomic changes were primarily cell type specific, involving multiple cell types, most prominently interhemispheric and callosal-projecting neurons, interneurons within superficial laminae, and distinct glial reactive states involving oligodendrocytes, microglia, and astrocytes. Autism-associated GRN drivers and their targets were enriched in rare and common genetic risk variants, connecting autism genetic susceptibility and cellular and circuit alterations in the human brain.
Most genetic variants associated with psychiatric disorders are located in noncoding regions of the genome. To investigate their functional implications, we integrate epigenetic data from the PsychENCODE Consortium and other published sources to construct a comprehensive atlas of candidate brain cis-regulatory elements. Using deep learning, we model these elements’ sequence syntax and predict how binding sites for lineage-specific transcription factors contribute to cell type–specific gene regulation in various types of glia and neurons. The elements’ evolutionary history suggests that new regulatory information in the brain emerges primarily via smaller sequence mutations within conserved mammalian elements rather than entirely new human- or primate-specific sequences. However, primate-specific candidate elements, particularly those active during fetal brain development and in excitatory neurons and astrocytes, are implicated in the heritability of brain-related human traits. Additionally, we introduce PsychSCREEN, a web-based platform offering interactive visualization of PsychENCODE-generated genetic and epigenetic data from diverse brain cell types in individuals with psychiatric disorders and healthy controls.
Human evolution is characterized by rapid brain enlargement and the emergence of unique cognitive abilities. Besides its distinctive cytoarchitectural organization and extensive inter-neuronal connectivity, the human brain is also defined by high rates of synaptic, mainly glutamatergic, transmission, and energy utilization. While these adaptations’ origins remain elusive, evolutionary changes occurred in synaptic glutamate metabolism in the common ancestor of humans and apes via the emergence of GLUD2, a gene encoding the human glutamate dehydrogenase 2 (hGDH2) isoenzyme. Driven by positive selection, hGDH2 became adapted to function upon intense excitatory firing, a process central to the long-term strengthening of synaptic connections. It also gained expression in brain astrocytes and cortical pyramidal neurons, including the CA1-CA3 hippocampal cells, neurons crucial to cognition. In mice transgenic for GLUD2, theta-burst-evoked long-term potentiation (LTP) is markedly enhanced in hippocampal CA3-CA1 synapses, with patch-clamp recordings from CA1 pyramidal neurons revealing increased sNMDA receptor currents. D-lactate blocked LTP enhancement, implying that glutamate metabolism via hGDH2 potentiates L-lactate-dependent glia–neuron interaction, a process essential to memory consolidation. The transgenic (Tg) mice exhibited increased dendritic spine density/synaptogenesis in the hippocampus and improved complex cognitive functions. Hence, enhancement of neuron–glia communication, via GLUD2 evolution, likely contributed to human cognitive advancement by potentiating synaptic plasticity and inter-neuronal connectivity.
The neocortex is a multi-layered structure that commands the brain higher functions in mammals generally, and in humans, it is essential for consciousness and cognition. The question about how the human brain works still without an answer where it is related to the underlying brain architecture-function relationship. Particularly, the structure of the neocortex that determines in larger part the brain network dynamics. In this work, some cortical regions were studied to reveal its architecture features unique to the human brain. Such features were previously reported on the transcriptome level for one cortical region in humans compared to other primates like chimpanzees and macaque. Using immunohistochemistry, some of these human-unique features were investigated in the current study over two human cortical regions; supramarginal gyrus and anterior cingulate cortex to show the human-specific regional differences over the cyto-expression patterns of these markers in terms of abundance, cell types and cortical layer specificity. Despite having high histological heterogeneity, this approach did not reveal big differences between studied regions over the investigated markers, suggesting that differences may present on the level function of each marker rather than the cyto-expression one.
In a more comprehensive manner, the whole transcriptome over cortical layers two to six was studied and analyzed in the anterior prefrontal cortex and primary visual cortex areas of the human neocortex using unsupervised sectioning followed by RNA sequencing. This approach revealed differences in the gene expression level of the human-specific cortical layers markers previously described and also for the whole transcriptome between the cortical layers of the studied regions. The most considerable differences were observed in internal layers of the neocortex specifically layer three and five that previously reported to harbor the highest-change in cortical layers-genes specificity between human and other primates, suggesting that these layers may be the sites for unique molecular or architecture differences between human and other primates as well as sites of differences between human neocortex regions.
At tripartite synapses, astrocytes are in close contact with neurons and contribute to various functions, from synaptic transmission, maintenance of ion homeostasis, and glutamate uptake to metabolism. However, disentangling the precise contribution of astrocytes to those phenomena and the underlying biochemical mechanisms is remarkably challenging. This notably results from their highly ramified morphology, the nanoscopic size of the majority of astrocyte processes, and the poorly understood information encoded by their spatiotemporally diverse calcium signals. This book chapter presents selected computational models of the involvement of astrocytes in glutamatergic transmission. The goal of this chapter is to present representative models of astrocyte function in conjunction with the biological questions they can investigate.
Astrocytes represent a diverse and morphologically complex group of glial cells critical for shaping and maintaining nervous system homeostasis, as well as responding to injuries. Understanding the origins of astroglial heterogeneity, originated from a limited number of progenitors, has been the focus of many studies. Most of these investigations have centered on protoplasmic and pial astrocytes, while the clonal relationship of fibrous astrocytes or juxtavascular astrocytes has remained relatively unexplored. In this study, we sought to elucidate the morphological diversity and clonal distribution of astrocytes across adult cortical layers, with particular emphasis on their ontogenetic origins. Using the StarTrack lineage tracing tool, we explored the characteristics of adult astroglial clones derived from single and specific progenitors at various embryonic stages. Our results revealed a heterogeneous spatial distribution of astroglial clones, characterized by variations in location, clonal size, and rostro–caudal dispersion. While a considerable proportion of clones were confined within specific cortical layers, others displayed sibling cells crossing layer boundaries. Notably, we observed a correlation between clone location and developmental stage at earlier embryonic stages, although this relationship diminished in later stages. Fibrous astrocyte clones were exclusively confined to the corpus callosum. In contrast, protoplasmic or juxtavascular clones were located in either the upper or lower cortical layers, with certain clones displayed sibling cells distributed across both regions. Our findings underscore the developmental origins and spatial distribution of astroglial clones within cortical layers, providing new insights into the interplay between their morphology, clonal sizes, and progenitor heterogeneity.
Biological systems are necessarily dissipative structures in the long run, and dissipative structures are far from equilibrium and homeostasis: order (periodicity) and disorder (non-linear variability) are “coexisting dynamic states”. The common epistemological habit of modern molecular biology is to reduce an observed phenotype or function to a molecular entity, such as a gene, protein or pathway, which have become the embodiment of causation in biology. In the emerging framework of gene network architecture the attractor nature of distinct cell phenotypes, explains a series of cell behaviors that are not easily accounted for by linear molecular pathways. It explains why cell-type specific genome-wide expression profiles, defined by the values of thousands of variables, are so reliably established during differentiation as if orchestrated by an invisible hand: the self-organizing and self-stabilizing property of biologically significant gene expression profiles is a natural feature conferred by attractors. In the human placental mammal, the embryonic cell cycle and intrauterine development process rests on one of the most effective dynamics to regulate the living, sometimes approaching and sometimes diverging chaos, i.e. a controlled chaos dynamics. Biological system’s development, namely each stage of the embryo development, is characterized by the presence of one-to-many attractors, toward which the developmental dynamic variables trajectories are rapidly approaching from all the points of its phase space. Symmetry propagation and symmetry breaking are essential processes in biological morphogenesis, in metazoan evolution and development. Within embryogenesis, the amniotic fluid (AF) should be treated as biological water in a super-coherent state and may act as an inherently dynamical entity endowed by a proper non-linear dynamics, that creates a biochemistry not governed by random collisions between molecules, but by a code of mutual recognition and recall among molecules based on long-distance electromagnetic interaction. For convenience, a GLOSSARY of terms extrapolated from the body of the text can be consulted at the end of the article.
Neurons are highly specialized for circuit activity. Their unique structure and function make them very vulnerable to small fluctuations in the composition of the extracellular space. A very important process is synaptic integration, which is the most energy-consuming process of the neuronal circuit. As the synapses are very often far from the cell body, a dynamic energy supply is a problem. For these and other challenges, the brain has an elaborate system of support or glial cells which in addition can act as partners in signaling pathways. The major group of glia are astrocytes, which have their own elaborate structure with domains and constitute a syncytium. They also cover the blood–brain barrier with endfeet. Their architecture destines them to be the prime partner of neurons in homeostasis and signaling. Another glial cell group is oligodendrocytes and their precursor cells. Oligodendrocytes specialize for myelination, whereas oligodendrocyte precursor cells are more complicated as they are on the receiving end of neuronal presynaptic endings. Finally, microglia are macrophages trapped in the brain after the establishment of the blood–brain barrier. They adapted to this peculiar environment by not only playing the part of a resident macrophage waiting for pathological challenges but also being involved in neuronal signaling. Three fluid systems are irrigating the brain. The blood supply thins out into fine processes, whose endothelial cells are the location of specific exchange systems and of the blood–brain barrier. The cerebrospinal fluid is created by the choroid plexus and migrates by bulk flow. It is in free exchange with the parenchyma and empties into the lymph and venous system, depending on pressure gradients. The glymphatic system is a convection system, from the perivascular arterial space through the glial syncytium and extracellular space toward several exit passages, venous system, and lymphatic system and on the way possibly mixing with cerebrospinal fluid. It is dependent on aquaporin channels and the dimensions of the extracellular space. That space is almost doubled during sleep, which eases the removal of waste products like β-amyloid peptide.
Astrocytes, once considered passive support cells in the central nervous system, are now recognized as dynamic contributors to neuronal processes. They play pivotal roles in regulating synaptic transmission, modulating excitability, and influencing synapse formation. These non-neuronal cells release gliotransmitters like glutamate, affecting synaptic activity. Dysfunctions in astrocytes are linked to neurodegenerative and psychiatric disorders. In neurodegenerative disorders like Alzheimer's and Parkinson's, astrocytic dysfunction plays distinct roles. While astrocytes may not significantly contribute to Alzheimer's progression, they are involved in neuroinflammation, Aβ metabolism, and calcium regulation. Conversely, in Parkinson's, astrocytes contribute to mitochondrial dysfunction, impacting dopaminergic neurons. This comprehensive exploration sheds light on the intricate and multifaceted roles of astrocytes in cognition and their potential implications for therapeutic interventions in neurological and psychiatric conditions.
Astrocytes are the most proliferate glial cells in the central nervous system (CNS); they are considered as the supporting cells in the CNS, and play a big role in behavioral, circuit, and synaptic functions. Astrocytes are also important for neuronal repair, neurogenesis, and survival. Astrocytes play a main role in brain protection, by maintaining a regulated ion balance and blood flow, and preserving an antioxidant functions in brain. In this chapter, the authors elaborated an overview of the role of astrocytes on the developing brain.
Astrocytes play a significant role in the working memory (WM) mechanism, yet their contribution to spiking neuron-astrocyte networks (SNAN) is underexplored. This study proposes a non-probabilistic SNAN incorporating a self-repairing (SR) mechanism through endocannabinoid pathways to facilitate WM function. Four experiments were conducted with different damaging patterns, replicating close-to-realistic synaptic impairments. Simulation results suggest that the SR process enhances WM performance by improving the consistency of neuronal firing. Moreover, the intercellular astrocytic [Ca]²⁺ transmission via gap junctions improves WM and SR processes. With increasing damage, WM and SR activities initially fail for non-matched samples and then for smaller and minimally overlapping matched samples. Simulation results also indicate that the inclusion of the SR mechanism in both random and continuous forms of damage improves the resilience of the WM by approximately 20%. This study highlights the importance of astrocytes in synaptically impaired networks.
Electrophysiological characterization of live human tissue from epilepsy patients has been performed for many decades. Although initially these studies sought to understand the biophysical and synaptic changes associated with human epilepsy, recently, it has become the mainstay for exploring the distinctive biophysical and synaptic features of human cell-types. Both epochs of these human cellular electrophysiological explorations have faced criticism. Early studies revealed that cortical pyramidal neurons obtained from individuals with epilepsy appeared to function “normally” in comparison to neurons from non-epilepsy controls or neurons from other species and thus there was little to gain from the study of human neurons from epilepsy patients. On the other hand, contemporary studies are often questioned for the “normalcy” of the recorded neurons since they are derived from epilepsy patients. In this review, we discuss our current understanding of the distinct biophysical features of human cortical neurons and glia obtained from tissue removed from patients with epilepsy and tumors. We then explore the concept of within cell-type diversity and its loss (i.e., “neural homogenization”). We introduce neural homogenization to help reconcile the epileptogenicity of seemingly “normal” human cortical cells and circuits. We propose that there should be continued efforts to study cortical tissue from epilepsy patients in the quest to understand what makes human cell-types “human”.
Non-invasive mapping of cellular pathology can provide critical diagnostic and prognostic information. Recent developments in diffusion MRI have produced new tools for examining tissue microstructure at a level well below the imaging resolution. Here, we report the use of diffusion time (t)-dependent diffusion kurtosis imaging (tDKI) to simultaneously assess the morphology and transmembrane permeability of cells and their processes in the context of pathological changes in hypoxic-ischemic brain (HI) injury. Through Monte Carlo simulations and cell culture organoid imaging, we demonstrate feasibility in measuring effective size and permeability changes based on the peak and tail of tDKI curves. In a mouse model of HI, in vivo imaging at 11.7T detects a marked shift of the tDKI peak to longer t in brain edema, suggesting swelling and beading associated with the astrocytic processes and neuronal neurites. Furthermore, we observed a faster decrease of the tDKI tail in injured brain regions, reflecting increased membrane permeability that was associated with upregulated water exchange upon astrocyte activation at acute stage as well as necrosis with disrupted membrane integrity at subacute stage. Such information, unavailable with conventional diffusion MRI at a single t, can predict salvageable tissues. For a proof-of-concept, tDKI at 3T on an ischemic stroke patient suggested increased membrane permeability in the stroke region. This work therefore demonstrates the potential of tDKI for in vivo detection of the pathological changes in microstructural morphology and transmembrane permeability after ischemic injury using a clinically translatable protocol.
Astrocytes are in contact with the vasculature, neurons, oligodendrocytes and microglia, forming a local network with various functions critical for brain homeostasis. One of the primary responders to brain injury are astrocytes as they detect neuronal and vascular damage, change their phenotype with morphological, proteomic and transcriptomic transformations for adaptive response. The role of astrocytic responses in brain dysfunction is not fully elucidated in adult, and even less described in the developing brain. Children are vulnerable to traumatic brain injury (TBI), which represents a leading cause of death and disability in the pediatric population. Pediatric brain trauma, even with mild severity, can lead to long-term health complications, such as cognitive impairments, emotional disorders and social dysfunction later in life. To date, the underlying pathophysiology is still not fully understood. In this review, we focus on the astrocytic response in pediatric TBI and propose a potential immune role of the astrocyte in response to trauma. We discuss the contribution of astrocytes in the local inflammatory cascades and secretion of various immunomodulatory factors involved in the recruitment of local microglial cells and peripheral immune cells through cerebral blood vessels. Taken together, we propose that early changes in the astrocyte phenotype can alter normal development of the brain, with long-term consequences on neurological outcomes, as described in preclinical models and patients.
While pain is sensed and conducted by neurons, including primary sensory neurons (nociceptors) and spinal cord pain transmission neurons, mounting evidence suggests that non-neuronal cells such as immune cells and glial cells in the peripheral nervous system (PNS) and central nervous system (CNS) play active roles in the pathogenesis and resolution of pain. We review how immune cells and glial cells interact with peripheral and central nociceptive neurons by secreting neuroactive signaling molecules (neuromodulators), leading to altered pain sensitivity. It is generally believed that chronic pain is maintained by central sensitization, that is, increased synaptic and neuronal responsiveness (synaptic or neural plasticity) in central pain pathways, after painful injuries and insults. Recent studies also suggest that central sensitization is driven by neuroinflammation. We also discuss how immune cells and glial cells regulate central sensitization and neuroinflammation in the context of chronic pain.KeywordsAstrocytesB cellsDRGFibroblastsMacrophagesMast cellsMicrogliaNeutrophilsOligodendrocytesSatellite glial cellsSchwann’s cellsSpinal cordT cells
Pathological changes in the medial prefrontal cortex (mPFC) and astrocytes are closely associated with Alzheimer's disease (AD). Voluntary running has been found to effectively delay AD. However, the effects of voluntary running on mPFC astrocytes in AD are unclear. A total of 40 10-month-old male amyloid precursor protein/presenilin 1 (APP/PS1) mice and 40 wild-type (WT) mice were randomly divided into control and running groups, and the running groups underwent voluntary running for 3 months. Mouse cognition was assessed by the novel object recognition (NOR), Morris water maze (MWM), and Y maze tests. The effects of voluntary running on mPFC astrocytes were investigated using immunohistochemistry, immunofluorescence, western blotting, and stereology. APP/PS1 mice performed significantly worse than WT mice in the NOR, MWM, and Y maze tests, and voluntary running improved the performance of APP/PS1 mice in these tests. The total number of mPFC astrocytes was increased, cell bodies were enlarged, and protrusion number and length were increased in AD mice compared with WT mice, but there was no difference in component 3 (C3) levels in the mPFC (total mPFC level); however, C3 and S100B levels in astrocytes were increased in AD mice. Voluntary running reduced the total number of astrocytes and S100B levels in astrocytes and increased the density of PSD95+ puncta in direct contact with astrocyte protrusions in the APP/PS1 mouse mPFC. Three months of voluntary running inhibited astrocyte hyperplasia and S100B expression in astrocytes, increased the density of synapses in contact with astrocytes, and improved cognitive function in APP/PS1 mice.
Neurodegenerative diseases are broadly characterized neuropathologically by the degeneration of vulnerable neuronal cell types in a specific brain region. The degeneration of specific cell types has informed on the various phenotypes/clinical presentations in someone suffering from these diseases. Prominent neurodegeneration of specific neurons is seen in polyglutamine expansion diseases including Huntington's disease (HD) and spinocerebellar ataxias (SCA). The clinical manifestations observed in these diseases could be as varied as the abnormalities in motor function observed in those who have Huntington's disease (HD) as demonstrated by a chorea with substantial degeneration of striatal medium spiny neurons (MSNs) or those with various forms of spinocerebellar ataxia (SCA) with an ataxic motor presentation primarily due to degeneration of cerebellar Purkinje cells. Due to the very significant nature of the degeneration of MSNs in HD and Purkinje cells in SCAs, much of the research has centered around understanding the cell autonomous mechanisms dysregulated in these neuronal cell types. However, an increasing number of studies have revealed that dysfunction in non-neuronal glial cell types contributes to the pathogenesis of these diseases. Here we explore these non-neuronal glial cell types with a focus on how each may contribute to the pathogenesis of HD and SCA and the tools used to evaluate glial cells in the context of these diseases. Understanding the regulation of supportive and harmful phenotypes of glia in disease could lead to development of novel glia-focused neurotherapeutics.
Huntington's disease (HD) is a fatal, monogenic, autosomal dominant neurodegenerative disease caused by a polyglutamine‐encoding CAG expansion in the huntingtin (HTT) gene that results in mutant huntingtin proteins (mHTT) in cells throughout the body. Although large parts of the central nervous system (CNS) are affected, the striatum is especially vulnerable and undergoes marked atrophy. Astrocytes are abundant within the striatum and contain mHTT in HD, as well as in mouse models of the disease. We focus on striatal astrocytes and summarize how they participate in, and contribute to, molecular pathophysiology and disease‐related phenotypes in HD model mice. Where possible, reference is made to pertinent astrocyte alterations in human HD. Astrocytic dysfunctions related to cellular morphology, extracellular ion and neurotransmitter homeostasis, and metabolic support all accompany the development and progression of HD, in both transgenic mouse and human cellular and chimeric models of HD. These findings reveal the potential for the therapeutic targeting of astrocytes so as to restore synaptic as well as tissue homeostasis in HD. Elucidation of the mechanisms by which astrocytes contribute to HD pathogenesis may inform a broader understanding of the role of glial pathology in neurodegenerative disorders and, by so doing, enable new strategies of glial‐directed therapeutics.
Is the human brain simply a scaled-up version of the mouse brain? This thesis investigates the comparative aspects of structural connectivity in human, monkey and mouse brain using relatively novel three-dimensional electron microscopy technique. We found evidence that the human nerve cells are composed of an increased number of interneurons that is two- to- three times higher compared to mouse. This, in effect, results in a massively increased connectivity between the inhibitory interneurons that is nearly absent in mouse. This, for the first time, points to a network innovation that is unique to the human cortical networks. This discovery encourages a new focus of studies on the functional relevance and impact of such connectivity features, with significance for fundamental as well as clinical neuroscience.
Protoplasmic astrocytes are increasingly thought to interact extensively with neuronal elements in the brain and to influence their activity. Recent reports have also begun to suggest that physiologically, and perhaps functionally, diverse forms of these cells may be present in the CNS. Our current understanding of astrocyte form and distribution is based predominately on studies that used the astrocytic marker glial fibrillary acidic protein (GFAP) and on studies using metal-impregnation techniques. The prevalent opinion, based on studies using these methods, is that astrocytic processes overlap extensively and primarily share the underlying neuropil. However, both of these techniques have serious shortcomings for visualizing the interactions among these structurally complex cells. In the present study, intracellular injection combined with immunohistochemistry for GFAP show that GFAP delineates only ∼15% of the total volume of the astrocyte. As a result, GFAP-based images have led to incorrect conclusions regarding the interaction of processes of neighboring astrocytes. To investigate these interactions in detail, groups of adjacent protoplasmic astrocytes in the CA1 stratum radiatum were injected with fluorescent intracellular tracers of distinctive emissive wavelengths and analyzed using three-dimensional (3D) confocal analysis and electron microscopy. Our findings show that protoplasmic astrocytes establish primarily exclusive territories. The knowledge of how the complex morphology of protoplasmic astrocytes affects their 3D relationships with other astrocytes, oligodendroglia, neurons, and vasculature of the brain should have important implications for our understanding of nervous system function.
We report the existence and distribution of an unusual type of projection neuron, a large, spindle-shaped cell, in layer Vb
of the anterior cingulate cortex of pongids and hominids. These spindle cells were not observed in any other primate species
or any other mammalian taxa, and their volume was correlated with brain volume residuals, a measure of encephalization in
higher primates. These observations are of particular interest when considering primate neocortical evolution, as they reveal
possible adaptive changes and functional modifications over the last 15–20 million years in the anterior cingulate cortex,
a region that plays a major role in the regulation of many aspects of autonomic function and of certain cognitive processes.
That in humans these unique neurons have been shown previously to be severely affected in the degenerative process of Alzheimer’s
disease suggests that some of the differential neuronal susceptibility that occurs in the human brain in the course of age-related
dementing illnesses may have appeared only recently during primate evolution.
The numerical density of neurons and glial cells was estimated in visual area 18 of the adult human cerebral cortex and compared with that of area 17. Blocks of areas 17 and 18 came from the same brains and this allowed the comparison of 1) neuronal and glial numerical densities through the whole cortical depth with calculation of the neuron/glia ratio, 2) neuronal and glial numbers under one square millimeter of cortical surface, and 3) neuronal numerical densities in three groups of identified layers. The mean neuronal density is approximately 40,000 neurons/mm3 in area 17 and 31,500/m3 in area 18. The mean glial density is around 27,000/mm3 in area 17 and 32,000/mm3 in area 18. This gives a neuron/glia ratio of approximately 1.5 in area 17 and of 1.0 in area 18, but the total cellular density is similar in both areas. There are about 90,000 neurons and 64,000 glial cells under one square millimeter of cortical surface in area 17, and some 73,000 neurons and 74,000 glial cells in area 18. The higher neuronal density in area 17 is found through the whole depth of cortex and does not seem to be more pronounced in layer IVc of area 17 compared to layer IV in area 18 than in the groups of layers II-III and V-VI.
Neurotransmitter released from neurons is known to signal to neighbouring neurons and glia. Here we demonstrate an additional signalling pathway in which glutamate is released from astrocytes and causes an NMDA (N-methyl-D-aspartate) receptor-mediated increase in neuronal calcium. Internal calcium was elevated and glutamate release stimulated by application of the neuroligand bradykinin to cultured astrocytes. Elevation of astrocyte internal calcium was also sufficient to induce glutamate release. To determine whether this released glutamate signals to neurons, we studied astrocyte-neuron co-cultures. Bradykinin significantly increased calcium levels in neurons co-cultured with astrocytes, but not in solitary neurons. The glutamate receptor antagonists D-2-amino-5-phosphonopentanoic acid and D-glutamylglycine prevented bradykinin-induced neuronal calcium elevation. When single astrocytes were directly stimulated to increase internal calcium and release glutamate, calcium levels of adjacent neurons were increased; this increase could be blocked by D-glutamylglycine. Thus, astrocytes regulate neuronal calcium levels through the calcium-dependent release of glutamate.
We report the existence and distribution of an unusual type of projection neuron, a large, spindle-shaped cell, in layer Vb of the anterior cingulate cortex of pongids and hominids. These spindle cells were not observed in any other primate species or any other mammalian taxa, and their volume was correlated with brain volume residuals, a measure of encephalization in higher primates. These observations are of particular interest when considering primate neocortical evolution, as they reveal possible adaptive changes and functional modifications over the last 15-20 million years in the anterior cingulate cortex, a region that plays a major role in the regulation of many aspects of autonomic function and of certain cognitive processes. That in humans these unique neurons have been shown previously to be severely affected in the degenerative process of Alzheimer's disease suggests that some of the differential neuronal susceptibility that occurs in the human brain in the course of age-related dementing illnesses may have appeared only recently during primate evolution.
Neurogenesis continues in the mammalian subventricular zone (SVZ) throughout life. However, the signaling and cell-cell interactions required for adult SVZ neurogenesis are not known. In vivo, migratory neuroblasts (type A cells) and putative precursors (type C cells) are in intimate contact with astrocytes (type B cells). Type B cells also contact each other. We reconstituted SVZ cell-cell interactions in a culture system free of serum or exogenous growth factors. Culturing dissociated postnatal or adult SVZ cells on astrocyte monolayers-but not other substrates-supported extensive neurogenesis similar to that observed in vivo. SVZ precursors proliferated rapidly on astrocytes to form colonies containing up to 100 type A neuroblasts. By fractionating the SVZ cell dissociates with differential adhesion to immobilized polylysine, we show that neuronal colony-forming precursors were concentrated in a fraction enriched for type B and C cells. Pure type A cells could migrate in chains but did not give rise to neuronal colonies. Because astrocyte-conditioned medium alone was not sufficient to support SVZ neurogenesis, direct cell-cell contact between astrocytes and SVZ neuronal precursors may be necessary for the production of type A cells.
The least known aspect of the functional architecture of hippocampal microcircuits is the quantitative distribution of synaptic inputs of identified cell classes. The complete dendritic trees of functionally distinct interneuron types containing parvalbumin (PV), calbindin D 28k (CB), or calretinin (CR) were reconstructed at the light microscopic level to describe their geometry, total length, and laminar distribution. Serial electron microscopic reconstruction and postembedding GABA immunostaining was then used to determine the density of GABA-negative asymmetrical (excitatory) and GABA-positive symmetrical (inhibitory) synaptic inputs on their dendrites, somata, and axon initial segments. The total convergence and the distribution of excitatory and inhibitory inputs were then calculated using the light and electron microscopic data sets.
The three populations showed characteristic differences in dendritic morphology and in the density and distribution of afferent synapses. PV cells possessed the most extensive dendritic tree (4300 μm) and the thickest dendrites. CR cells had the smallest dendritic tree (2500 μm) and the thinnest shafts. The density of inputs as well as the total number of excitatory plus inhibitory synapses was several times higher on PV cells (on average, 16,294) than on CB (3839) or CR (2186) cells. The ratio of GABAergic inputs was significantly higher on CB (29.4%) and CR (20.71%) cells than on PV cells (6.4%). The density of inhibitory terminals was higher in the perisomatic region than on the distal dendrites.
These anatomical data are essential to understand the distinct behavior and role of these interneuron types during hippocampal activity patterns and represent fundamental information for modeling studies.
Although astrocytes constitute nearly half of the cells in our brain, their function is a long-standing neurobiological mystery.
Here we show by quantal analyses, FM1-43 imaging, immunostaining, and electron microscopy that few synapses form in the absence
of glial cells and that the few synapses that do form are functionally immature. Astrocytes increase the number of mature,
functional synapses on central nervous system (CNS) neurons by sevenfold and are required for synaptic maintenance in vitro.
We also show that most synapses are generated concurrently with the development of glia in vivo. These data demonstrate a
previously unknown function for glia in inducing and stabilizing CNS synapses, show that CNS synapse number can be profoundly
regulated by nonneuronal signals, and raise the possibility that glia may actively participate in synaptic plasticity.
Glial cells are emerging from the background to become more prominent in
our thinking about integration in the nervous system. Given that glial cells
associated with synapses integrate neuronal inputs and can release transmitters
that modulate synaptic activity, it is time to rethink our understanding of
the wiring diagram of the nervous system. It is no longer appropriate to consider
solely neuron–neuron connections; we also need to develop a view of
the intricate web of active connections among glial cells, and between glia
and neurons. Without such a view, it might be impossible to decode the language
of the brain.
Protoplasmic astrocytes are increasingly thought to interact extensively with neuronal elements in the brain and to influence their activity. Recent reports have also begun to suggest that physiologically, and perhaps functionally, diverse forms of these cells may be present in the CNS. Our current understanding of astrocyte form and distribution is based predominantly on studies that used the astrocytic marker glial fibrillary acidic protein (GFAP) and on studies using metal-impregnation techniques. The prevalent opinion, based on studies using these methods, is that astrocytic processes overlap extensively and primarily share the underlying neuropil. However, both of these techniques have serious shortcomings for visualizing the interactions among these structurally complex cells. In the present study, intracellular injection combined with immunohistochemistry for GFAP show that GFAP delineates only approximately 15% of the total volume of the astrocyte. As a result, GFAP-based images have led to incorrect conclusions regarding the interaction of processes of neighboring astrocytes. To investigate these interactions in detail, groups of adjacent protoplasmic astrocytes in the CA1 stratum radiatum were injected with fluorescent intracellular tracers of distinctive emissive wavelengths and analyzed using three-dimensional (3D) confocal analysis and electron microscopy. Our findings show that protoplasmic astrocytes establish primarily exclusive territories. The knowledge of how the complex morphology of protoplasmic astrocytes affects their 3D relationships with other astrocytes, oligodendroglia, neurons, and vasculature of the brain should have important implications for our understanding of nervous system function.
We revealed the structural features of astrocytes by means of light microscopy, confocal laser scanning microscopy and high voltage electron microscopy, and estimated their numerical densities in the mouse hippocampus. The high voltage electron microscope examinations of Golgi-impregnated astrocytes clearly disclosed their fine leaflet-like processes in the masses occupied by individual astrocytes. The intracellular injection of two different fluorescent tracers into two neighboring astrocytes revealed that each astrocyte occupied a discrete area with a limited overlap only at its peripheral portion. In a quantitative analysis using an optical dissector, the numerical densities of astrocytes identified as S100-immunoreactive cells were only slightly different in their areal and laminar distributions. The numerical densities were higher in the stratum lacunosum-moleculare and dentate hilus, while they were slightly lower in the principal cell layers than the average (24.2 x 10(3) mm(-3)) in whole hippocampal regions. As for the dorsoventral difference, the numerical densities were significantly larger at the ventral level in the dentate gyrus, whereas such tendency was not apparent in the hippocampus proper. The projection area of the astrocytes estimated from Golgi-impregnated samples was roughly in inverse relation to the numerical densities; the areas in the stratum lacunosum-moleculare were somewhat smaller than the other layers, where the numerical densities were high. The present study indicates that astrocytes are distributed rather evenly without any prominent areal or laminar differences and that the individual astrocytes have their own domains; the periphery of the domain of a given astrocyte is interdigitated intricately with the processes of adjacent astrocytes whereas its inner core portion is not penetrated by them.
Glutamate is the principal excitatory neurotransmitter of the central nervous system, but many studies have expanded its functional repertoire by showing that glutamate receptors are present in a variety of non-excitable cells. How does glutamate receptor activation modulate their activity? Do non-excitable cells release glutamate, and, if so, how? These questions remain enigmatic. Here, we review the current knowledge on glutamatergic signalling in non-neuronal cells, with a special emphasis on astrocytes.
The cellular mechanisms underlying functional hyperemia--the coupling of neuronal activation to cerebral blood vessel responses--are not yet known. Here we show in rat cortical slices that the dilation of arterioles triggered by neuronal activity is dependent on glutamate-mediated [Ca(2+)](i) oscillations in astrocytes. Inhibition of these Ca(2+) responses resulted in the impairment of activity-dependent vasodilation, whereas selective activation--by patch pipette--of single astrocytes that were in contact with arterioles triggered vessel relaxation. We also found that a cyclooxygenase product is centrally involved in this astrocyte-mediated control of arterioles. In vivo blockade of glutamate-mediated [Ca(2+)](i) elevations in astrocytes reduced the blood flow increase in the somatosensory cortex during contralateral forepaw stimulation. Taken together, our findings show that neuron-to-astrocyte signaling is a key mechanism in functional hyperemia.
Little is known about the expression and possible functions of unopposed gap junction hemichannels in the brain. Emerging evidence suggests that gap junction hemichannels can act as stand-alone functional channels in astrocytes. With immunocytochemistry, dye uptake, and HPLC measurements, we show that astrocytes in vitro express functional hemichannels that can mediate robust efflux of glutamate and aspartate. Functional hemichannels were confirmed by passage of extracellular lucifer yellow (LY) into astrocytes in nominal divalent cation-free solution (DCFS) and the ability to block this passage with gap junction blocking agents. Glutamate/aspartate release (or LY loading) in DCFS was blocked by multivalent cations (Ca2+, Ba2+, Sr2+, Mg2+, and La3+) and by gap junction blocking agents (carbenoxolone, octanol, heptanol, flufenamic acid, and 18alpha-glycyrrhetinic acid) with affinities close to those reported for blockade of gap junction intercellular communication. Glutamate efflux via hemichannels was also accompanied by greatly reduced glutamate uptake. Glutamate release in DCFS, however, was not significantly mediated by reversal of the glutamate transporter: release did not saturate and was not blocked by glutamate transporter blockers. Control experiments in DCFS precluded glutamate release by volume-sensitive anion channels, P2X7 purinergic receptor pores, or general purinergic receptor activation. Blocking intracellular Ca2+ mobilization by BAPTA-AM or thapsigargin did not inhibit glutamate release in DCFS. Divalent cation removal also induced glutamate release from intact CNS white matter (acutely isolated optic nerve) that was blocked by carbenoxolone, suggesting the existence of functional hemichannels in situ. Our results indicated that astrocyte hemichannels could influence CNS levels of extracellular glutamate with implications for normal and pathological brain function.
The appearance of the neocortex, its expansion, and its differentiation in mammals, represents one of the principal episodes in the evolution of the vertebrate brain. One of the fundamental questions in neuroscience is what is special about the neocortex of humans and how does it differ from that of other species? It is clear that distinct cortical areas show important differences within both the same and different species, and this has led to some researchers emphasizing the similarities whereas others focus on the differences. In general, despite of the large number of different elements that contribute to neocortical circuits, it is thought that neocortical neurons are organized into multiple, small repeating microcircuits, based around pyramidal cells and their input-output connections. These inputs originate from extrinsic afferent systems, excitatory glutamatergic spiny cells (which include other pyramidal cells and spiny stellate cells), and inhibitory GABAergic interneurons. The problem is that the neuronal elements that make up the basic microcircuit are differentiated into subtypes, some of which are lacking or highly modified in different cortical areas or species. Furthermore, the number of neurons contained in a discrete vertical cylinder of cortical tissue varies across species. Additionally, it has been shown that the neuropil in different cortical areas of the human, rat and mouse has a characteristic layer specific synaptology. These variations most likely reflect functional differences in the specific cortical circuits. The laminar specific similarities between cortical areas and between species, with respect to the percentage, length and density of excitatory and inhibitory synapses, and to the number of synapses per neuron, might be considered as the basic cortical building bricks. In turn, the differences probably indicate the evolutionary adaptation of excitatory and inhibitory circuits to particular functions.
Astrocytes establish rapid cell-to-cell communication through the release of chemical transmitters. The underlying mechanisms and functional significance of this release are, however, not well understood. Here we identify an astrocytic vesicular compartment that is competent for glutamate exocytosis. Using postembedding immunogold labeling of the rat hippocampus, we show that vesicular glutamate transporters (VGLUT1/2) and the vesicular SNARE protein, cellubrevin, are both expressed in small vesicular organelles that resemble synaptic vesicles of glutamatergic terminals. Astrocytic vesicles, which are not as densely packed as their neuronal counterparts, can be observed in small groups at sites adjacent to neuronal structures bearing glutamate receptors. Fluorescently tagged VGLUT-containing vesicles were studied dynamically in living astrocytes by total internal reflection fluorescence (TIRF) microscopy. After activation of metabotropic glutamate receptors, astrocytic vesicles underwent rapid (milliseconds) Ca(2+)- and SNARE-dependent exocytic fusion that was accompanied by glutamate release. These data document the existence of a Ca(2+)-dependent quantal glutamate release activity in glia that was previously considered to be specific to synapses.
Cortical pyramidal cells, while having a characteristic morphology, show marked phenotypic variation in primates. Differences have been reported in their size, branching structure and spine density between cortical areas. In particular, there is a systematic increase in the complexity of the structure of pyramidal cells with anterior progression through occipito-temporal cortical visual areas. These differences reflect area-specific specializations in cortical circuitry, which are believed to be important for visual processing. However, it remains unknown as to whether these regional specializations in pyramidal cell structure are restricted to primates. Here we investigated pyramidal cell structure in the visual cortex of the tree shrew, including the primary (V1), second (V2) and temporal dorsal (TD) areas. As in primates, there was a trend for more complex branching structure with anterior progression through visual areas in the tree shrew. However, contrary to the trend reported in primates, cells in the tree shrew tended to become smaller with anterior progression through V1, V2 and TD. In addition, pyramidal cells in V1 of the tree shrew are more than twice as spinous as those in primates. These data suggest that variables that shape the structure of adult cortical pyramidal cells differ among species.
In terms of breadth, depth, and originality, this work ranked Cajal with Pasteur and Darwin as giants of 19th century biology. Summarizing almost 20 years of intense research, Cajal systematically described the cellular organization of almost every part of the nervous system in all five classes of vertebrate, and provided a synthetic account of their embryogenesis as well. This revolutionary work laid a broad foundation for modern neuroscience. Neuroscientists, neurologists, psychologists, computer and cognitive scientists, and nonspecialists will find this work of great use. Modern neuroanatomical terminology is used wherever possible, while attempting to preserve the style of the original text. Summarizing almost 20 years of intense research, Cajal systematically described the cellular organization of almost every part of the nervous system in all five classes of vertebrate, and provided a synthetic account of their embryogenesis as well. This work was revolutionary and laid a broad foundation for modern neuroscience because two new concepts - the neuron doctrine and the law of functional polarity - were used to interpret the data, and because the resulting interpretations opened vast new fields of research with profound clinical implications in neurology and psychiatry. In terms of breadth, depth and originality, this work is second only to that of Vesalius in the history of anatomy, and ranked Cajal with Pasteur and Darwin as the giants of 19th century biology. In many ways, the Histology is as valuable today as when it was written, and these volumes will be of use to a broad spectrum of neuroscientists, neurologists, psychologists, and computer and cognitive scientists. To make this work accessible to non specialists, the translators have used modern neuroanatomical terminology wherever possible, while attempting to preserve the style of the original text. They have also provided extensive cross-referencing of synonyms in the index, and notes to clarify difficult passages.
A new technique combining microfluorometric DNA assays with differential cell counts was used to quantitate the intralaminar distribution of neuronal and non-neuronal cells (chiefly glial) in rat somatosensory cortex (Charles River 250 gm males, C D® strain). The intracortical amounts of DNA per unit fresh volume were calculated from the DNA contents of serial frozen slices of known volume sampled serially from the pial surface to white matter in frozen cortical cylinders; respective amounts per unit solids were calculated from predetermined dry weights of the slices. Cell counts were performed on serial horizontal sections from formalin-fixed cylinders stained by Nissl's method. Neuronal DNA and glial DNA were calculated based on the percentages of the respective cells counted.
Total DNA averaged 5.43 μg/mg dry weight (1.19 μg mm3 fresh volume). Values were highest in layers II and IV. Neuronal DNA paralleled total DNA in its intracortical distribution and showed distinct peaks in layers II and IV. Glial DNA showed an even distribution. Glia exceeded neurons only in layers I and VIc. The mean neuron/glia ratio was 2.5. This method gives a more precise estimate of the absolute numbers of neurons and glia than can be obtained by histological methods alone, since DNA assays eliminate the need to correct the histological counts for volume changes during fixation and staining.
Rapid removal of glutamate from the extracellular space is required for the survival and normal function of neurons. Although glutamate transporters are expressed by all CNS cell types, astrocytes are the cell type primarily responsible for glutamate uptake. Astrocyte glutamate uptake also plays a role in regulating the activity of glutamatergic synapses. Lastly, release of glutamate from astrocytes, via transporter reversal and other routes, can contribute to glutamate receptor activation. This review examines the mechanisms of astrocyte glutamate uptake and release, with particular focus on high-affinity Na+-dependent transporters. Transporter regulation, energetics, and physiological roles are discussed. GLIA 32:1–14, 2000. Published 2000 Wiley-Liss, Inc.
Astrocytes and oligodendrocytes in the isolated intact mature rat optic nerve have been computer imaged in three dimensions by laser scanning confocal microscopy of single cells, dye-filled with lysinated rhodamine dextran (LRD). Our results illustrate the first application of these techniques to an intact CNS white matter tract and provide comparative data for previous studies on neonatal rat optic nerve (Butt and Ransom: Glia 2:470-475, 1989; Butt and Ransom: J Comp Neurol 338:141-158, 1993). The combined use of intracellular injection of LRD and confocal imaging significantly improves the resolution of glial cell structure, particularly that of mature astrocytes, for a number of reasons. 1) Single mature dye-filled glia can be imaged, because LRD does not pass through gap junctions. 2) The entire process field of astrocytes can be visualized in a single two-dimensional image. 3) Cell images can be rotated through 360 degrees in all planes to provide a new perspective of glial cell structure in the intact tissue. 4) Reconstruction of optical sections, within a narrow focal plane, provides a high definition and resolution of the finer details of glial morphology. Using these techniques, three astrocyte subclasses were distinguished on morphological criteria. It is the conclusion of this study that the majority of these forms represent a single population of fibrous astrocytes which are well-suited to perform the multiple functions attributed to astrocytes in the CNS. The morphology of mature myelin-forming oligodendrocytes was also described.(ABSTRACT TRUNCATED AT 250 WORDS)
The pathogenesis of sporadic amyotrophic lateral sclerosis (ALS) is unknown, but defects in synaptosomal high-affinity glutamate transport have been observed. In experimental models, chronic loss of glutamate transport can produce a loss of motor neurons and, therefore, could contribute to the disease. With the recent cloning of three glutamate transporters, i.e., EAAC1, GLT-1, and GLAST, it has become possible to determine if the loss of glutamate transport in ALS is subtype specific. We developed C-terminal, antioligopeptide antibodies that were specific for each glutamate transporter. EAAC1 is selective for neurons, while GLT-1 and GLAST are selective for astroglia. Tissue from various brain regions of ALS patients and controls were examined by immunoblot or immunocytochemical methods for each transporter subtype. All tissue was matched for age and postmortem delay. GLT-1 immunoreactive protein was severely decreased in ALS, both in motor cortex (71% decrease compared with control) and in spinal cord. In approximately a quarter of the ALS motor cortex specimens, the loss of GLT-1 protein (90% decrease from control) was dramatic. By contrast, there was only a modest loss (20% decrease from control) of immunoreactive protein EAAC1 in ALS motor cortex, and there was no appreciable change in GLAST. The minor loss of EAAC1 could be secondary to loss of cortical motor neurons. As a comparison, glial fibrillary acidic protein, which is selectively localized to astroglia, was not changed in ALS motor cortex. Because there is no loss of astroglia in ALS, the dramatic abnormalities in GLT-1 could reflect a primary defect in GLT-1 protein, a secondary loss due to down regulation, or other toxic processes.
Although astrocytes have been considered to be supportive, rather than transmissive, in the adult nervous system, recent studies
have challenged this assumption by demonstrating that astrocytes possess functional neurotransmitter receptors. Astrocytes
are now shown to directly modulate the free cytosolic calcium, and hence transmission characteristics, of neighboring neurons.
When a focal electric field potential was applied to single astrocytes in mixed cultures of rat forebrain astrocytes and neurons,
a prompt elevation of calcium occurred in the target cell. This in turn triggered a wave of calcium increase, which propagated
from astrocyte to astrocyte. Neurons resting on these astrocytes responded with large increases in their concentration of
cytosolic calcium. The gap junction blocker octanol attenuated the neuronal response, which suggests that the astrocytic-neuronal
signaling is mediated through intercellular connections rather than synaptically. This neuronal response to local astrocytic
stimulation may mediate local intercellular communication within the brain.
Tissue samples from the caudate nucleus were obtained from eight children (eight to 172 months of age) who underwent hemispherectomies for the relief of intractable seizures. Neurophysiological, pharmacological and morphological properties of caudate neurons were characterized by intracellular recordings in an in vitro slice preparation. These properties were compared with those of tissue obtained from animal studies. Electrophysiological properties of human caudate neurons that were similar to those of cat caudate and rat neostriatal cells included resting membrane potential, input resistance, action potential rise time, fall time, duration and action potential afterhyperpolarization amplitude, as well as the general characteristics of locally evoked synaptic responses. Properties that were different included action potential amplitudes and time-constants. Human caudate neurons also displayed responses similar to those of cat caudate or rat neostriatal cells to manipulation of excitatory amino acid receptor systems and to dopamine application. Kynurenic acid, a broad-spectrum excitatory amino acid receptor antagonist, decreased the amplitude of evoked synaptic responses, indicating that they were partially mediated by excitatory amino acids. In Mg2+ free Ringer's solution, the amplitudes and durations of postsynaptic responses were increased and bursts of action potentials were induced. These effects were mediated by activation of N-methyl-D-aspartate receptors since they were blocked by 2-amino-5-phosphonovalerate, a specific N-methyl-D-aspartate-receptor antagonist. Iontophoretic application of N-methyl-D-aspartate also induced membrane oscillations and bursts in almost all caudate neurons. Dopamine decreased the amplitude of postsynaptic responses, an effect antagonized by domperidone, a selective D2 dopamine receptor antagonist. Developmentally, the greatest change was an increase in action potential amplitude, although input resistance decreased and action potential afterhyperpolarization amplitude increased. Postsynaptic responses were similar across age. All but one of the caudate neurons identified by intracellular injection of biocytin or Lucifer Yellow were medium-sized spiny cells. These experiments show that human caudate neurons display a number of electrophysiological properties similar to rat neostriatal or cat caudate neurons recorded in brain slices. Furthermore, few electrophysiological parameters changed significantly over the age period examined suggesting that the human caudate at eight months displays many of the neuronal functions of the more mature caudate nucleus.
Glial fibrillary acidic protein (GFAP) mRNA was examined by RNA blot hybridization in three age groups of two cohorts of male F-344 rats and in 47 human postmortem brain samples. GFAP mRNA increased in the hippocampus and striatum of 24 versus 6- to 7-month-old rats. Another astrocytic molecular marker, glutamine synthetase mRNA, did not change with age in rat brain. Rat GFAP mRNA prevalence was inversely correlated with serum testosterone but not correlated with serum corticosterone. In human hippocampus, frontal and temporal cortex, GFAP mRNA also increased in older (60-79 years) compared with middle-aged (25-59 years) individuals. In contrast, mitochondrial cytochrome oxidase subunit 1 mRNA did not change between age groups in any region. By combining the three regions for further analysis, GFAP mRNA increased with age irregardless of gender, alcoholism in the middle-aged group, or whether brains were classified as normal or neuropathologic (excluding Alzheimer's disease pathology). These data indicate that increased GFAP protein or GFAP-immunoreactive astrocytes in rats and humans may result from transcriptional or post-transcriptional regulation and extend the number to three species (including mouse) showing an increase in GFAP mRNA with age. Factors that are known to regulate GFAP mRNA expression in young brains are considered as possible causes of age-related increases.
The availability of neocortical tissue obtained during brain surgery has allowed for detailed studies of the membrane and synaptic properties of neurons maintained in vitro in a slice preparation. Many of the findings obtained in these studies are summarized here. The majority of the basic electrophysiological properties appear to be similar when human and rodent neurons are compared. However, some notable exceptions regarding specific membrane properties have been reported. Since the majority of the material used in these studies is obtained from epileptic patients, several neuroscientists have tried to determine whether this tissue retains any sign of epileptogenicity when analyzed in vitro. Abnormal synaptic activity was only seen in a fraction of neurons near identified anatomical foci, including tumors, or within neocortical areas that displayed abnormal electrographic activity in situ. This cellular activity included both the presence of all-or-none and graded synaptic bursts. Epileptiform activity comparable to that seen in rodent tissue has been obtained in vitro using several pharmacological procedures including the disinhibition and the Mg(2+)-free model. In conclusion, electrophysiological and pharmacological studies of the human neocortex obtained during surgery have so far been unsuccessful in isolating any definite cellular mechanism that may account for the expression of the epileptiform activity in situ. Nevertheless, these studies have provided valuable information on the cellular and synaptic properties of human neocortex under normal conditions, and following experimental procedures capable of increasing neuronal excitability.
Chandelier cells are cortical GABAergic interneurons with a unique synaptic specificity enabling them to exert a strong inhibitory influence on pyramidal cells. By using immunocytochemistry for the calcium-binding protein calbindin D-28k in the human temporal neocortex, we have found numerous immunoreactive processes that were identified as chandelier cell axon terminals. This was a striking find since in previous immunocytochemical studies of the primate neocortex, chandelier cell axon terminals had been shown to be immunoreactive for another calcium-binding protein, parvalbumin, and colocalization studies indicate that parvalbumin and calbindin are present in almost completely separate neuronal populations. Here, we present double-label immunofluorescence experiments showing that parvalbumin and calbindin immunoreactivities are colocalized in certain neurons that include a subpopulation of chandelier cells whose cell bodies are located mainly in layers V and VI of the human temporal neocortex. The results suggest a selective laminar distribution of neurochemical subtypes of chandelier cells which is a peculiar feature of the organization of the human neocortex.
At variance with the rat, previous observations disclosed the presence of long interlaminar astroglial processes in the cerebral cortex of adult nonhuman primates. To examine its presence in human cerebral cortex, samples of frontal and temporal cerebral cortices were obtained during programmed brain surgery from a young patient with an intraventricular astrocytoma, and from one young and two adult patients with frontal and temporal lobe focal epilepsy, respectively. Samples of the visual cortex were also obtained at an autopsy of an 84-year-old woman without any known neurological disease. Brain tissues were processed for GFAP-IR immunocytochemistry. Long, interlaminar, GFAP-IR astroglial processes of usually 300-500 microm, but occasionally reaching almost 1,000 microm, were observed. These processes resembled those previously described in the cerebral cortex of adult New World monkeys. Available data suggest that they may represent a predominant characteristic in postnatal primate cerebral cortex. EM analysis of club-like endings disclosed a multilamellar organization of GFAP-IR intermediate filaments, and the presence of mitochondria and amorphous, electron dense material. Their possible function is yet to be determined.
We have examined the distribution of double bouquet cell axons, immunocytochemically stained for the calcium-binding proteins calretinin and calbindin D-28k in the human temporal neocortex, in relation to bundles of myelinated axons (originating from pyramidal cells) and the colocalization of these calcium-binding proteins. The large number and regularity of distribution of double bouquet cell axons was clearly visualized in tangential sections from cortical layers III--V. In these sections, we estimated that the mean number +/- standard deviation of double bouquet cell axons per 10,000 microns2 was 11.65 +/- 0.44 with a mean diameter of 12.10 +/- 0.63 microns and a mean center-to-center spacing of 29.8 +/- 0.91 microns. These values are very similar to those previously reported in the monkey neocortex. The distribution of double bouquet cell axons was closely related to bundles of myelinated axons; there was overlapping with basically a one-to-one correspondence. Finally, double-label immunofluorescence experiments revealed that the vast majority of double bouquet cell axons immunoreactive for calbindin were also stained for calretinin. Since relatively few cell somata were double-labeled in the human temporal cortex, we concluded that double bouquet cells may represent a significant subpopulation of neurons that colocalize these calcium-binding proteins.
Unlabelled:
Long astroglial processes traversing several cortical laminae appear to be characteristic of primate brains. Whether interlaminar processes develop as a modification of radial glia or are truly postnatal elements stemming from stellate astroglia, could be assessed by analyzing their early developmental stages. A survey of glial fibrillar acidic protein immunoreactive (GFAP-IR) astroglial interlaminar processes in the cerebral cortex of Ceboidea monkeys at various postnatal developmental ages, and in human cortical samples of a ten day and a seven year old child disclosed that such processes develop postnatally. At one month of age GFAP-IR interlaminar processes in monkeys were scarce and short in most frontal, parietal or occipital (striate) cortical areas, except for sulcal (principal and orbital sulci) and temporal cortical areas. Some processes were weakly positive for vimentin, and these were most abundant in ventral temporal cortical areas. At two months of age processes were present in all these areas, albeit in restricted patches and significantly shorter than in adults. The expression of this pattern was increased at seven months of age. At three years of age almost every area showed abundant processes and with lengths comparable to the adult Ceboidea individuals. In humans, at 10 days of age long interlaminar processes were readily apparent in a frontal cortex sample, becoming most apparent at the age of seven years although not reaching yet the adult characteristics as described previously.
Conclusions:
(1) GFAP-IR interlaminar processes develop postnatally, thus typifying a subtype of the classical stellate forms; (2) they bear no obvious direct relationship with radial glia; (3) their development is not contemporary among the various cortical regions. These long cellular processes represent an addition to those already described for other astroglial cell types in the adult mammalian brain (Golgi-Bergmann glia, tanicytes, Muller cells).
Neocortical astrocytes make two types of gap junctions, intercellular ones create a functional syncytium, while reflexive gap junctions mediate autocellular coupling and serve unknown functions (Rohlmann and Wolff, 1996). Here, the question is addressed whether solitary astrocytes in vitro express connexin43 (Cx43) and establish gap junctions in the absence of intercellular contacts. In all media conditions tested, immunocytochemistry visualized Cx43-expression and gap junctions irrespective of the presence or absence of intercellular contacts. Reflexive gap junctions were associated with mechanical junctions (adherent spots and fascia adherens) connecting surface membranes and cytoskelal components, respectively. Both were characteristically located along incompletely separated borders between developing processes and/or branches. In addition, Cx43-immunoreactivity was found on some non-junctional membranes: i) intracellular vesicle clusters sited to forming processes and at the basis of filopodia; ii) the surface membrane of filopodial subpopulations usually appearing in bunches. Results suggest changes in the resumptive role of Cx43 in cultivated astrocytes: 1) Cx43 is not confined to intercellular gap junctions, it may even selectively compose reflexive ones; 2) from intracellular stores (vesicle aggregates), Cx43 may be incorporated into the surface membrane of filopodia; 3) by contacting other parts of the same cell surface (or neighboring cells), filopodia and membrane patches carrying Cx43-half channels may be essential in initial steps of gap junction formation; 4) the distribution of reflexive gap junctions is compatible with the hypothesis that autocellular coupling serves reorganization of cytoskeleton during the formation of cell processes and branches; 5) in general, gap junctions may be important for coordinating the cytoskeleton across intercellular contacts and within cells with complex shape.
We studied physiological properties of glial cells from acute slices of biopsies from patients operated for intractable mesio-temporal lobe epilepsy using whole-cell patch-clamp recordings. Cells were filled with Lucifer Yellow (LY) during recordings to allow morphological reconstruction and immunohistochemical cell identification. Seizure-associated astrocytes had complex, arborized, highly branched processes giving them a stellate appearance, and cells stained intensely for the intermediate filament GFAP as previously reported for 'reactive' astrocytes. GFAP-positive astrocytes from epilepsy biopsies consistently expressed voltage-activated, TTX-sensitive Na+ channels that showed fast activation and inactivation kinetics. Unlike comparison astrocytes, derived from tissues that were not associated with seizure foci, these astrocytes expressed Na+ channels at densities sufficient to generate slow action potentials (spikes) in current clamp studies. In these cells, the ratio of Na+ to K+ conductance was consistently 3-4-fold higher than in comparison human or control rat astrocytes. Four of 17 astrocytes from epilepsy patients versus 14/14 from control rat hippocampus and four of five in comparison human tissue showed a lack of inwardly rectifying K+ currents, which in normal astrocytes are implicated in the control of extracellular K+ levels. These results suggest that astrocytes surrounding seizure foci differ in morphological and physiological properties, and that glial K+ buffering could be impaired at the seizure focus, thus contributing to the pathophysiology of seizures.
This study identifies fundamental anatomical features of primary visual cortex, area V1 of macaque monkey cerebral cortex, i.e., features that are present in area V1 of phylogenetically distant mammals of quite different lifestyle and features that are common to other regions of cortex. We compared anatomical constituents of macaque V1 with V1 of members of the two principal marsupial lines, the dunnart and the quokka, that diverged from the eutherian mammalian line over 135 million years ago. Features of V1 common to both macaque and marsupials were then compared with anatomical features we have previously described for macaque prefrontal cortex. Despite large differences in overall area and thickness of V1 cortex between these animals, the absolute size of pyramidal neurons is remarkably similar, as are their specific dendritic branch patterns and patterns of distribution of intrinsic axons. Pyramidal neuron patchy connections exist in the supragranular V1 in both the marsupial quokka and macaque as well as in macaque prefrontal cortex. Several specific types of aspinous interneurons are common to area V1 in both marsupial and macaque and are also present in macaque prefrontal cortex. Spiny stellate cells are a common feature of the thalamic-recipient, mid-depth lamina 4 of V1 in all three species. Because these similarities exist despite the very different lifestyles and evolutionary histories of the animals compared, this finding argues for a highly conserved framework of cellular detail in macaque primary visual cortex rather than convergent evolution of these features.
Rapid removal of glutamate from the extracellular space is required for the survival and normal function of neurons. Although glutamate transporters are expressed by all CNS cell types, astrocytes are the cell type primarily responsible for glutamate uptake. Astrocyte glutamate uptake also plays a role in regulating the activity of glutamatergic synapses. Lastly, release of glutamate from astrocytes, via transporter reversal and other routes, can contribute to glutamate receptor activation. This review examines the mechanisms of astrocyte glutamate uptake and release, with particular focus on high-affinity Na(+)-dependent transporters. Transporter regulation, energetics, and physiological roles are discussed.
Over the past two years, ATP has clearly been shown to act as a co-transmitter with GABA, glycine and probably glutamate in the central nervous system. Our understanding of the ATP-gated P2X receptors is progressing rapidly, and the pharmacology, stoichiometry and subunit combinations of heteropolymeric P2X channels has been substantially elucidated.
Following brain injury, and during the process of neurodegeneration, a reactive astrocytic proliferation occurs. This is accompanied by an increase in the synthesis of neuropeptides, cytokines, growth factors and glial fibrillary acidic protein (GFAP), a cell-specific marker for reactive astrocytes. Astrocytes are extensively coupled by gap junctions of the Cx43 connexin subtype. Several studies have shown that in severe trauma, coupling between astrocytes may add to the spread of the damaged area. In this study we ask whether the astrocytosis which is a feature of other neurodegenerative diseases also occurs in mesial temporal lobe epilepsy (MTLE) and whether it is accompanied by an increase in astrocytic communication through an upregulation of Cx43 gap junction channel proteins. In order to examine the astrocytic response and the expression pattern of Cx43 protein, double immunohistochemical labeling studies were undertaken using antibodies against GFAP and Cx43 applied to human hippocampal tissue resected from patients with MTLE, and to normal human control hippocampal tissue. Immunofluorescent labeling of astrocytes and Cx43 was examined using confocal laser scanning microscopy. The images obtained were quantitatively analysed and reconstructed using three-dimensional volume rendering. The results of this study have established that not only is astrocytosis greater in MTLE-affected tissues than previously suggested, but it is accompanied by a highly significant increase in astrocytic Cx43 protein levels. We hypothesize that this surprisingly large upregulation in Cx43 may exacerbate generalized seizures in the progression of MTLE.
During an investigation of the mechanisms through which the local environment controls the fate specification of adult neural stem cells, we discovered that adult astrocytes from hippocampus are capable of regulating neurogenesis by instructing the stem cells to adopt a neuronal fate. This role in fate specification was unexpected because, during development, neurons are generated before most of the astrocytes. Our findings, together with recent reports that astrocytes regulate synapse formation and synaptic transmission, reinforce the emerging view that astrocytes have an active regulatory role--rather than merely supportive roles traditionally assigned to them--in the mature central nervous system.
A palisade of long, interlaminar astroglial processes in supragranular layers of the cerebral cortex is characteristic of adult individuals of anthropoid species. In the present study, this distinctive cytoarchitectonic feature was analyzed in tissue deriving from the neocortex of cases affected by Alzheimer's disease (n=14) and age-matched control cases (n=10). Samples of different cortical areas, and in particular prefrontal, temporal and striate fields, were analyzed. Astroglia was labeled by glial fibrillary acidic protein immunoreactivity, that allowed a clear distinction between the classical, stellate intralaminar astroglia and the interlaminar glial processes. The occurrence and relative density of neuritic plaques were ascertained in the same specimens with Bielchowsky staining. In most cortical regions of cases diagnosed as severe Alzheimer's disease by the donor institutions, interlaminar astroglia was found to be markedly altered or absent, and replaced by hypertrophic intralaminar astrocytes. Cases diagnosed as milder or uncertain Alzheimer's disease showed a less consistent involvement of the interlaminar glial palisade. Alterations of the interlaminar palisade in the cortex affected by Alzheimer's disease did not strictly correlate with the density of neuritic plaques in the examined specimens. The findings indicate that loss/severe disruption of the interlaminar palisade of astroglial processes is part of the array of neuropathological changes occurring in the cerebral cortex during Alzheimer's disease. In addition, our data indicate that different types of neocortical astrocytes (namely intralaminar and interlaminar astrocytes) respond differently to the pathobiology of Alzheimer's disease in the neocortex, inasmuch as interlaminar processes tend to disappear while intralaminar processes become reactive.
Gap junctions are widely expressed in the various cell types of the central nervous system. These specialized membrane intercellular junctions provide the morphological support for direct electrical and biochemical communication between adjacent cells. This intercellular coupling is controlled by neurotransmitters and other endogenous compounds produced and released in basal as well as in pathological situations. Changes in the expression and the function of connexins are associated with number of brain pathologies and lesions suggesting that they could contribute to the expansion of brain damages. The purpose of this review is to summarize data presently available concerning gap junctions and the expression and function of connexins in different cell types of the central nervous system and to present their physiopathological relevance in three major brain dysfunctions: inflammation, epilepsy and ischemia.
beta-Amyloid(1-42) (A beta 42), a major component of amyloid plaques, accumulates within pyramidal neurons in the brains of individuals with Alzheimer's disease (AD) and Down syndrome. In brain areas exhibiting AD pathology, A beta 42-immunopositive material is observed in astrocytes. In the present study, single- and double-label immunohistochemistry were used to reveal the origin and fate of this material in astrocytes. Our findings suggest that astrocytes throughout the entorhinal cortex of AD patients gradually accumulate A beta 42-positive material and that the amount of this material correlates positively with the extent of local AD pathology. A beta 42-positive material within astrocytes appears to be of neuronal origin, most likely accumulated via phagocytosis of local degenerated dendrites and synapses, especially in the cortical molecular layer. The co-localization of neuron-specific proteins, alpha 7 nicotinic acetylcholine receptor and choline acetyltransferase, in A beta 42-burdened, activated astrocytes supports this possibility. Our results also suggest that some astrocytes containing A beta 42-positive deposits undergo lysis, resulting in the formation of astrocyte-derived amyloid plaques in the cortical molecular layer in brain regions showing moderate to advanced AD pathology. These astrocytic plaques can be distinguished from those arising from neuronal lysis by virtue of their smaller size, their nearly exclusive localization in the subpial portion of the molecular layer of the cerebrocortex, and by their intense glial fibrillary acidic protein immunoreactivity. Overall, A beta 42 accumulation and the selective lysis of A beta 42-burdened neurons and astrocytes appear to make a major contribution to the observed amyloid plaques in AD brains.
Astrocytes have traditionally been considered ancillary, satellite cells of the nervous system. However, work over the past decade has revealed that they interact with the vasculature to form a gliovascular network that might organize not only the structural architecture of the brain but also its communication pathways, activation, thresholds and plasticity. The net effect is that astroglia demarcate gray matter regions, both cortical and subcortical, into functional compartments whose internal activation thresholds and external outputs are regulated by single glial cells. The array of these astrocyte-delimited microdomains along the capillary microvasculature allows the formation of higher-order gliovascular units, which serve to match local neural activity and blood flow while regulating neuronal firing thresholds through coordinative glial signaling. By these means, astrocytes might establish the functional as well as the structural architecture of the adult brain.
Evidence for "cable-like" processes stemming from astroglial cells in the supragranular cerebral cortex has been recently presented. In addition to what could be called the "general mammalian-like" astroglial architecture (the so-called "panglial syncytium") of the cerebral cortex, composed of typical stellate astrocytes (intralaminar astrocytes), the anthropoid species, mostly catarrhines, show a manifest vertical, radial distribution of long (interlaminar) astroglial processes. It can be tentatively proposed that evolutionary pressures resulted in the progressive appearance, in primates, of a new type of glial cell. Its soma has a superficial location and unusually long cellular processes that invade, in a predominant radial fashion, the supragranular region of the cerebral cortex. Their existence has been ignored for more than a century. On the neuronal side, modular (columnar) organization of the cerebral cortex may represent an evolutionary acquisition that could optimize communication and information processing, with the least volume compromise in terms of wiring. Yet, for such columns to be functionally operative, adequate isolation from neighboring units would be required. A "mass" operation of the astroglial architecture would tend to compromise spatial definition and the degrees of freedom of such columnar modules. It is proposed that the presence of a "palisade" of interlaminar glial processes represents a relatively recent evolutionary event, instrumental for the optimization of the modular (columnar) organization of the cerebral cortex. It is interesting that the supragranular cortical region has undergone the largest growth among mammalian species during brain evolution, and has been associated with a crucial role in cortico-cortical interactions.
Amyloid plaques appear early during Alzheimer's disease (AD), and their development is intimately linked to activated astrocytes and microglia. Astrocytes are capable of accumulating substantial amounts of neuron-derived, amyloid beta(1-42) (Abeta42)-positive material and other neuron-specific proteins as a consequence of their debris-clearing role in response to local neurodegeneration. Immunohistochemical analyses have suggested that astrocytes overburdened with these internalized materials can eventually undergo lysis, and radial dispersal of their cytoplasmic contents, including Abeta42, can lead to the deposition of a persistent residue in the form of small, GFAP-rich, astrocytic amyloid plaques, first appearing in the molecular layer of the cerebral cortex. Microglia, most of which appear to be derived from blood monocytes and recruited from local blood vessels, rapidly migrate into and congregate within neuritic and dense-core plaques, but not diffuse plaques. Instead of internalizing and removing Abeta from plaques, microglia appear to contribute to their morphological and chemical evolution by facilitating the conversion of existing soluble and oligomeric Abeta within plaques to the fibrillar form. Abeta fibrillogenesis may occur largely within tiny, tube-like invaginations in the surface plasma membrane of microglia. These results highlight the therapeutic potential of blocking the initial intracellular accumulation of Abeta42 in neurons and astrocytes and inhibiting microglia-mediated assembly of fibrillar Abeta, which is particularly resistant to degradation in Alzheimer brain.
Cerebral blood flow (CBF) is coupled to neuronal activity and is imaged in vivo to map brain activation. CBF is also modified by afferent projection fibres that release vasoactive neurotransmitters in the perivascular region, principally on the astrocyte endfeet that outline cerebral blood vessels. However, the role of astrocytes in the regulation of cerebrovascular tone remains uncertain. Here we determine the impact of intracellular Ca(2+) concentrations ([Ca(2+)](i)) in astrocytes on the diameter of small arterioles by using two-photon Ca(2+) uncaging to increase [Ca(2+)](i). Vascular constrictions occurred when Ca(2+) waves evoked by uncaging propagated into the astrocyte endfeet and caused large increases in [Ca(2+)](i). The vasoactive neurotransmitter noradrenaline increased [Ca(2+)](i) in the astrocyte endfeet, the peak of which preceded the onset of arteriole constriction. Depressing increases in astrocyte [Ca(2+)](i) with BAPTA inhibited the vascular constrictions in noradrenaline. We find that constrictions induced in the cerebrovasculature by increased [Ca(2+)](i) in astrocyte endfeet are generated through the phospholipase A(2)-arachidonic acid pathway and 20-hydroxyeicosatetraenoic acid production. Vasoconstriction by astrocytes is a previously unknown mechanism for the regulation of CBF.
Astrocytes are highly complex cells that respond to a variety of external stimulations. One of the chief functions of astrocytes is to optimize the interstitial space for synaptic transmission by tight control of water and ionic homeostasis. Several lines of work have, over the past decade, expanded the role of astrocytes and it is now clear that astrocytes are active participants in the tri-partite synapse and modulate synaptic activity in hippocampus, cortex, and hypothalamus. Thus, the emerging concept of astrocytes includes both supportive functions as well as active modulation of neuronal output.