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A Physiology of neuronal-glial networking
Abstract
Neuronal-glial networks are the substrate for the brain function. Evolution of the nervous system resulted in the appearance of highly specialized neuronal web optimized for rapid information transfer. This neuronal web is embedded into glial syncytium, thereby creating sophisticated neuronal-glial circuitry were both types of neural cells are working in concert, ensuring amplification of brain computational power. In addition neuroglial cells are fundamental for control of brain homeostasis and they represent the intrinsic brain defence system, being thus intimately involved in pathogenesis of neurological diseases.
... Astrocytes are the primary homeostatic cells of the CNS (Verkhratsky andNedergaard, 2016, 2018), which are distributed throughout the brain and the spinal cord; in the nervous tissue these cells present a remarkable morphological, molecular and functional diversity, which was generally acknowledged from the very dawn of neuroglial research (Fig. 1). According to morpho-functional criteria astrocytes are sub-classified into (Fig. 2) Verkhratsky et al., 2019b): (i) radial glia, which are the pluripotent neural cells precursors that disappear at birth in mammals; (ii) protoplasmic astrocytes of grey matter; (iii) fibrous astrocytes of white matter; (iv) specialised astrocytes: (a) velate astrocytes, which are found in the brain areas densely packed with small neurones, for example in the olfactory bulb or in the granular layer of the cerebellar cortex, (b) perivascular and marginal astrocytes, localised near the pia mater, where they form endfeet with blood vessels (these astrocytes do not establish contacts with neurons and their main function is in establishing the pial and perivascular glia limitans barriers), (c) pituicytes, the astrocytes of the neurohypophysis, (d) Gomori astrocytes rich in iron and positive for Gomori's chrome alum hematoxylin staining identified in the hypothalamus and in the hippocampus and (e) surfaceassociated astrocytes associated with the cortical surface in the posterior prefrontal and amygdaloid cortex; (v) radial astrocytes, which include (a) Bergmann glia in the cerebellum, (b) Müller glia of the retina, (c) tanycytes of the hypothalamus, hypophysis and the raphe part of the spinal cord and (d) radial glia-like neural stem cells of the neurogenic niches; (vi) ependymocytes, choroid plexus cells and retinal pigment epithelial cells. ...
... Astrocytes possess receptors to all types of neurotransmitters and neuromodulators; although the expression of these receptors is tightly regulated by immediate neurochemical environment (Verkhratsky, 2010;Verkhratsky et al., 1998). Being equipped with all these receptors, astrocytes receive information associated with neuronal synaptic transmission, which triggers astroglial functional responses. ...
... The remarkable molecular diversity of astrocytes reflects their ability to express multiple cell-specific sets of neurotransmitter receptors, ion channels and transporters congruent with the homeostatic demands of their immediate environment, such as those associated with synaptic transmission (Hamilton and Attwell, 2010;Olsen et al., 2015;Verkhratsky, 2010;. Physiological stimulation of astroglial receptors trigger specific forms of glial excitability that are associated with spatio-temporally organised fluctuations of cytosolic concentration of ions. ...
Astrocytes are heterogeneous population of neural cells with diverse structural, functional and molecular characteristics responsible for homeostasis and protection of the central nervous system (CNS). Unlike neurones, astrocytes do not generate action potentials, but employ fluctuations of cytosolic ions as a substrate for their excitability. Ionic signals are associated with neuronal activity and these signals initiate an array of responses ranging from the activation of plasmalemmal homeostatic transporters to the secretion of numerous signalling molecules including neuromodulators, neurotransmitter precursors, metabolic substrates, trophic factors and cytokines. Thus, astrocytes regulate the synaptic connectivity of the neuronal networks by supporting neurotransmitter metabolism, synaptogenesis, synaptic elimination and synaptic plasticity contributing to cognitive processing including learning, memory, emotions and behaviour. Astroglia-specific regulatory pathways affect the most fundamental properties of neuronal networks from their excitability to synaptic connectivity. Thus, it is the concerted action of glia and neurones, which, by employing distinct mechanisms, produce behavioural outputs of the ultimate control centre that we call the brain.
... 14,15 The neurotransmitter receptor modalities expressed by astroglia are similar to those expressed by their neuronal neighbours and are most likely influenced by the local neurotransmitter environment. 16,17 Association of Astrocytes with Ion Channels K + release-related depolarization can be used by astrocytes to detect neuronal activation. Gap junctions connect astrocytes to nearby astrocytes, allowing ions and tiny molecules to flow between them. ...
... The involvement of genes conveyed by glial cells (such as oligodendrocytes, astrocytes, and/or microglia) is primarily responsible for AD. 17 Apolipoprotein E (APOE) is a critical genetic risk factor for late-onset AD. It causes β-amyloid deposition in the brain in healthy people. ...
... Whereas neurons are the major mediators for all aspects of brain function, glia, although abundantly seen, are usually considered passive bystanders that provide nutrient and support (Allen and Lyons, 2018;Kim et al., 2020;Perez-Catalan et al., 2021). Evolutionally, the percentage of glial cells increases with the complexity of organisms, from 16% in nematodes, 20% in Drosophila, 50% in mice, to 90% in human brains, suggesting that glia play a broader and more complex role (Verkhratsky, 2010;Zwarts et al., 2015;Losada-Perez, 2018;Yildirim et al., 2019;Doron and Goshen, 2020). Intriguingly, glial cells among these species are similar in the morphology and function. ...
... It has been widely recognized that glia are part of the tripartite synapse and respond to neuronal signals by calcium wave propagation, a functional way to relay signals to adjacent or distal glia via gap junctions (Kielian and Esen, 2004;Deitmer and Rose, 2010;Verkhratsky, 2010;De Bock et al., 2013;Mu et al., 2019;Spray et al., 2019). To further investigate whether neurotransmitters trigger change in genes involved in these aspects, a list of genes encoding channels, transporters, and gap junctions were compiled and analyzed ( Table 2). ...
Fundamental properties of neurons and glia are distinctively different. Neurons are excitable cells that transmit information, whereas glia have long been considered as passive bystanders. Recently, the concept of tripartite synapse is proposed that glia are structurally and functionally incorporated into the synapse, the basic unit of information processing in the brains. It has then become intriguing how glia actively communicate with the presynaptic and postsynaptic compartments to influence the signal transmission. Here we present a thorough analysis at the transcriptional level on how glia respond to different types of neurotransmitters. Adult fly glia were purified from brains incubated with different types of neurotransmitters ex vivo . Subsequent RNA-sequencing analyses reveal distinct and overlapping patterns for these transcriptomes. Whereas Acetylcholine (ACh) and Glutamate (Glu) more vigorously activate glial gene expression, GABA retains its inhibitory effect. All neurotransmitters fail to trigger a significant change in the expression of their synthesis enzymes, yet Glu triggers increased expression of neurotransmitter receptors including its own and nAChRs. Expressions of transporters for GABA and Glutamate are under diverse controls from DA, GABA, and Glu, suggesting that the evoked intracellular pathways by these neurotransmitters are interconnected. Furthermore, changes in the expression of genes involved in calcium signaling also functionally predict the change in the glial activity. Finally, neurotransmitters also trigger a general metabolic suppression in glia except the DA, which upregulates a number of genes involved in transporting nutrients and amino acids. Our findings fundamentally dissect the transcriptional change in glia facing neuronal challenges; these results provide insights on how glia and neurons crosstalk in a synaptic context and underlie the mechanism of brain function and behavior.
... Usually, the modality of neurotransmitter receptors expressed by astroglia matches that of their neuronal neighbours, and is most likely controlled by the local neurotransmitter environment. 54,448 For example, Bergmann glial cells express receptors that exactly match the modality of receptors expressed by Purkinje neurones. The repertoire of receptors is thus optimised to sense neurotransmitters released by neuronal afferents, which form synapses in the neurone-glial unit. ...
... Astrocytic expression of dopamine receptors is prominent in basal ganglia and ventral midbrain which utilise dopaminergic transmission, while astroglial expression of serotonin receptors is restricted to areas contacting serotonergic terminals. 159,448 Therefore, expression of astroglial receptors in vivo is regulated by neurochemical input, which makes astrocytes perceptive to signals specific for each particular region of the brain. Detected in the hippocampus, cortex, cerebellum, white matter, Bergmann glial cells, immature astrocytes Cationic Na þ /K þ channels or Na þ /K þ /Ca 2þ channels. ...
... This is mediated by the PAX6 gene, which is inhibited by miR-365, and its expression is reduced by long-term risperidone treatment [26,27]. Astrocytes also express nearly all neuronal receptors, though their expression depends on the main neurotransmitters released by the neighboring neurons [28]. This indicates that neuronal signaling may synchronize astrocytes for proper activities/functions, such as neurotransmitter removal or ion homeostasis. ...
... Here, we provide data regarding glial dysfunction, focusing in particular on epigenetic aberrations in major mental diseases; then, we present supporting evidence indicating that glia dysfunction might be linked to gut microbiome alterations in these diseases. Astrocytes also express nearly all neuronal receptors, though their expression depends on the main neurotransmitters released by the neighboring neurons [28]. This indicates that neuronal signaling may synchronize astrocytes for proper activities/functions, such as neurotransmitter removal or ion homeostasis. ...
The tissue-specific expression and epigenetic dysregulation of many genes in cells derived from the postmortem brains of patients have been reported to provide a fundamental biological framework for major mental diseases such as autism, schizophrenia, bipolar disorder, and major depression. However, until recently, the impact of non-neuronal brain cells, which arises due to cell-type-specific alterations, has not been adequately scrutinized; this is because of the absence of techniques that directly evaluate their functionality. With the emergence of single-cell technologies, such as RNA sequencing (RNA-seq) and other novel techniques, various studies have now started to uncover the cell-type-specific expression and DNA methylation regulation of many genes (e.g., TREM2, MECP2, SLC1A2, TGFB2, NTRK2, S100B, KCNJ10, and HMGB1, and several complement genes such as C1q, C3, C3R, and C4) in the non-neuronal brain cells involved in the pathogenesis of mental diseases. Additionally, several lines of experimental evidence indicate that inflammation and inflammation-induced oxidative stress, as well as many insidious/latent infectious elements including the gut microbiome, alter the expression status and the epigenetic landscapes of brain non-neuronal cells. Here, we present supporting evidence highlighting the importance of the contribution of the brain’s non-neuronal cells (in particular, microglia and different types of astrocytes) in the pathogenesis of mental diseases. Furthermore, we also address the potential impacts of the gut microbiome in the dysfunction of enteric and brain glia, as well as astrocytes, which, in turn, may affect neuronal functions in mental disorders. Finally, we present evidence that supports that microbiota transplantations from the affected individuals or mice provoke the corresponding disease-like behavior in the recipient mice, while specific bacterial species may have beneficial effects.
... One-way ANOVA with post hoc Tukey's test for multiple comparisons, (n ≥ 6 cells per cohort, One-way ANOVA with Tukey's multiple comparison test, *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001, ****P ≤ 0.0001). hyperactivity has been suggested to be a result of the changed microenvironment due to pro-inflammatory mediators, such as cytokines, reactive oxygen species and free radicals released from the activated astrocytes and glial cells [47,55]; this would lead to an altered K + ion homeostasis that would ultimately disrupt excitable membranes, rendering them more hyperactive due an accumulation of extracellular K + released from neurons, a direct impact from the reduced astrocytes function [47,55,69]. These alterations in the sub-and suprathreshold membrane properties, culminated in hyperactive membrane properties and an increase in the firing in our AD models observed in LEC and CA1 pyramidal cells; the increase in the firing frequency corroborates previous studies using other AD models [32]. ...
... These could be associated with alterations and down regulation of leak conductances responsible for governing the intrinsic firing of these cells. Furthermore, the altered membrane hyperactivity has been suggested to be a result of the changed microenvironment due to pro-inflammatory mediators, such as cytokines, reactive oxygen species and free radicals released from the activated astrocytes and glial cells [47,55]; this would lead to an altered K + ion homeostasis that would ultimately disrupt excitable membranes, rendering them more hyperactive due an accumulation of extracellular K + released from neurons, a direct impact from the reduced astrocytes function [47,55,69]. ...
The presubiculum (PRS) is an integral component of the perforant pathway that has recently been recognised as a relatively unscathed region in clinical Alzheimer’s disease (AD), despite neighbouring components of the perforant pathway, CA1 and the entorhinal cortex, responsible for formation of episodic memory and storage, showing severe hallmarks of AD including, amyloid-beta (Aβ) plaques, tau tangles and marked gliosis. However, the question remains whether this anatomical resilience translates into functional resilience of the PRS neurons. Using neuroanatomy combined with whole-cell electrophysiological recordings, we investigated whether the unique spatial profile of the PRS was replicable in two knock-in mouse models of AD, APPNL-F/NL-F, and APPNL-F/MAPTHTAU and whether the intrinsic properties and morphological integrity of the PRS principal neurons was maintained compared to the lateral entorhinal cortex (LEC) and hippocampal CA1 principal cells. Our data revealed an age-dependent Aβ and tau pathology with neuroinflammation in the LEC and CA1, but a presence of fleece-like Aβ deposits with an absence of tau tangles and cellular markers of gliosis in the PRS of the mouse models at 11–16 and 18–22 months. These observations were consistent in human post-mortem AD tissue. This spatial profile also correlated with functional resilience of strong burst firing PRS pyramidal cells that showed unaltered sub- and suprathreshold intrinsic biophysical membrane properties and gross morphology in the AD models that were similar to the properties of pyramidal cells recorded in age-matched wild-type mice (11–14 months). This was in contrast to the LEC and CA1 principal cells which showed altered subthreshold intrinsic properties such as a higher input resistance, longer membrane time constants and hyperexcitability in response to suprathreshold stimulation that correlated with atrophied dendrites in both AD models. In conclusion, our data show for the first time that the unique anatomical profile of the PRS constitutes a diffuse AD pathology that is correlated with the preservation of principal pyramidal cell intrinsic biophysical and morphological properties despite alteration of LEC and CA1 pyramidal cells in two distinct genetic models of AD. Understanding the underlying mechanisms of this resilience could be beneficial in preventing the spread of disease pathology before cognitive deficits are precipitated in AD.
... Astrocytes perform a wide variety of critical functions determining normal operation of the nervous tissue. Numerous receptors expressed in astrocytes allow them to sense neuronal activity [28], activation of these receptors trigger astrocytic ionic signalling, mainly mediated by changes in cytosolic concentration of Ca 2+ and Na + [29] which control a multitude of plasmalemmal "homeostatic" transporters [30]. In addition, astrocytic excitability is supported by second messengers such as ATP [31]. ...
... The role for glial cells, and for astrocytes in particular, in neuropathology of many neurodegenerative diseases is universally acknowledged [28,65]. The risk of AD is associated with genes mainly expressed by glial cells, either astrocytes, microglia and/or oligodendrocytes [66]. ...
Astrocytes perform a wide variety of essential functions defining normal operation of the
nervous system and are active contributors to the pathogenesis of neurodegenerative disorders such as Alzheimer’s among others. Recent data provide compelling evidence that distinct astrocyte states are associated with specific stages of Alzheimer´s disease. The advent of transcriptomics technologies enables rapid progress in the characterisation of such pathological astrocyte states. In this review, we provide an overview of the origin, main functions, molecular and morphological features of astrocytes in physiological as well as pathological conditions related to Alzheimer´s disease. We will also explore the main roles of astrocytes in the pathogenesis of Alzheimer´s disease and summarize
main transcriptional changes and altered molecular pathways observed in astrocytes during the course of the disease.
... Glial cells act as synapse formation controller, which plays a role in nerve activity (Houzel, 2014). Increased glial cells number is an indicator of a proper synapse function and may be associated with human intelligence (Verkhratsky, 2010). Initial glial cells establishment were started as early as the 28 th day of conception (Hepper, 2007). ...
... Connectivity between neuronal and glial cells includes analyzing , processing, storing and employing the received information in cognitive function. Proper information process in neuronal and glial cells connectivity showed brain function and intelligence (Verkhratsky, 2010). ...
Music stimulation is an important component for prenatal fetal development. Both pop and religious music are easy to listen and widely accepted in Indonesia. This study was to analyze the effect of Mozart, pop, and religious music exposure during pregnancy to the number of glial cells in the brain of Rattus norvegicus offspring. The samples were divided into three groups based on the exposure for each group, namely Mozart, pop, and religious music, duration of 60 minutes with 65dB intensity, initiated on the 10th day of pregnancy for 9 days in the soundproof chamber. Three brains of the offsprings were dissected and prepared for Hematoxylin-Eosin staining counted on 5 fields of view and 400 magnification strength.Different glial cells number of Rattus norvegicus brain between groups were observed. Mozart music (28,29) showed a highest mean and pop music (18,67) showed the lowest mean. Significant difference of the number of brain glial cells between Mozart music compared to pop and religious music groups were observed, with p value <0,005.The number of brain glial cells of Rattus norvegicus offsprings in the Mozart group were significantly higher than those in pop and religious groups.
... Importantly, however, central glial cells including astrocytes and microglia have been shown to influence a wide range of neural functions including nociception through neuronal-glial and glialglial interactions (Watkins et al., 2001;Volterra and Steinhäuser, 2004;Scholz and Woolf, 2007;Verkhratsky, 2010;Graeber and Christie, 2012). Astroglial cells express neurotransmitter receptors and exhibit Ca 2+ transients in response to glutamate, GABA, ATP and also endocannabinoids released by neurons (Perea et al., 2009;Parpura and Verkhratsky, 2012;Zorec et al., 2012;Bazargani and Attwell, 2016). ...
The endogenous cannabinoid 2-arachidonoylglycerol (2-AG) influences neurotransmission in the central nervous system mainly by activating type 1 cannabinoid receptor (CB1). Following its release, 2-AG is broken down by hydrolases to yield arachidonic acid, which may subsequently be metabolized by cyclooxygenase-2 (COX-2). COX-2 converts arachidonic acid and also 2-AG into prostanoids, well-known inflammatory and pro-nociceptive mediators. Here, using immunohistochemical and biochemical methods and pharmacological manipulations, we found that reactive spinal astrocytes and microglia increase the expression of COX-2 and the production of prostaglandin E2 when exposed to 2-AG. Both 2-AG and PGE2 evoke calcium transients in spinal astrocytes, but PGE2 showed 30% more efficacy and 55 times more potency than 2-AG. Unstimulated spinal dorsal horn astrocytes responded to 2-AG with calcium transients mainly through the activation of CB1. 2-AG induced exaggerated calcium transients in reactive astrocytes, but this increase in the frequency and area under the curve of calcium signals was only partially dependent on CB1. Instead, aberrant calcium transients were almost completely abolished by COX-2 inhibition. Our results suggest that both reactive spinal astrocytes and microglia perform an endocannabinoid-prostanoid switch to produce PGE2 at the expense of 2-AG. PGE2 in turn is responsible for the induction of aberrant astroglial calcium signals which, together with PGE2 production may play role in the development and maintenance of spinal neuroinflammation-associated disturbances such as central sensitization.
... Glial cells are the predominant cell type in the mammalian brain, contributing 50-60% of the brain's total mass, and are critical in maintaining the function and integrity of the surrounding neurons. This view is supported by the findings of closely-tied spatial proximity (Perea et al, 2014), bidirectional communication (Verkhratsky, 2010), and neurometabolic coupling of astrocytes with neurons at the pre-and post-synapse (Dienel, 2017;Lee et al, 2021). Through this association, the various perineural glial subtypes function to maintain the critical physiology and firing ability of the adjoining neurons (Heller and Rusakov, 2017) by providing the requisite structural and metabolic support, homeostatic balance, and defence against oxidative stress (Allen and Eroglu, 2017;Siracusa et al, 2019), consequently increasing the number of mature, and functional synapses on the neurons (Pfrieger, 2010;Pfrieger and Barres, 1997;Ullian et al, 2001). ...
The phospholipid and free fatty acid (FFA) composition of neuronal membranes plays a crucial role in learning and memory, but the mechanisms through which neuronal activity affects the brain's lipid landscape remain largely unexplored. The levels of saturated FFAs, particularly of myristic acid (C14:0), strongly increase during neuronal stimulation and memory acquisition, suggesting the involvement of phospholipase A1 (PLA1) activity in synaptic plasticity. Here, we show that genetic ablation of the PLA1 isoform DDHD2 in mice dramatically reduces saturated FFA responses to memory acquisition across the brain. Furthermore, DDHD2 loss also decreases memory performance in reward-based learning and spatial memory models prior to the development of neuromuscular deficits that mirror human spastic paraplegia. Via pulldown-mass spectrometry analyses, we find that DDHD2 binds to the key synaptic protein STXBP1. Using STXBP1/2 knockout neurosecre-tory cells and a haploinsufficient STXBP1 +/− mouse model of human early infantile encephalopathy associated with intellectual disability and motor dysfunction, we show that STXBP1 controls targeting of DDHD2 to the plasma membrane and generation of saturated FFAs in the brain. These findings suggest key roles for DDHD2 and STXBP1 in lipid metabolism and in the processes of synaptic plasticity, learning, and memory.
... Astroglia, being neural cells, are potentially capable of expressing all receptors to neurotransmitters, neurohormones, and neuromodulators as neurones do, which permits astroglial cells to perceive their neurochemical environment and sense signaling molecules released by neurones and other cells in the nervous tissue (Verkhratsky, 2010). Glia, similar to neurones, are endowed with both ionotropic and metabotropic receptors. ...
... During the development of the peripheral nervous system (PNS), neurons and glial cells form an integrated system, which is provided by an exclusive and reciprocal molecular network interaction and is able to maintain an efficient homeostasis, regulating the development and the physiology of both components [1,2]. During neurogenesis, glial cells provide distinct paracrine signalling to support neuronal survival, define the molecular domains of the axolemma and axonal diameter, and maintain an appropriate concentration of neurotransmitters in the neuronal environment [3,4]. ...
The cross talk between neurons and glial cells during development, adulthood, and disease, has been extensively documented. Among the molecules mediating these interactions, neurotransmitters play a relevant role both in myelinating and non-myelinating glial cells, thus resulting as additional candidates regulating the development and physiology of the glial cells. In this review, we summarise the contribution of the main neurotransmitter receptors in the regulation of the morphogenetic events of glial cells, with particular attention paid to the role of acetylcholine receptors in Schwann cell physiology. In particular, the M2 muscarinic receptor influences Schwann cell phenotype and the α7 nicotinic receptor is emerging as influential in the modulation of peripheral nerve regeneration and inflammation. This new evidence significantly improves our knowledge of Schwann cell development and function and may contribute to identifying interesting new targets to support the activity of these cells in pathological conditions.
... We consider neuroinflammation as a key process underlying catatonia as acute ill patients diagnosed with autoimmune diseases or infections sporadically present with catatonic symptoms (Cawkwell et al., 2021;Zain et al., 2021;Sakhardande et al., 2022). Microglia and astrocytes are sensitive to inflammation, its morphological change to M1-A1 respectively is known to cause connexins to decouple, neurons and oligodendrocytes injury by activation of complement and oxidative stress, and thus generating weak synaptic transmission, myelin destabilization, and excitatory-inhibitory imbalance (Orthmann-Murphy et al., 2008;Verkhratsky et al., 2009;Verkhratsky, 2010). On the other hand, some cases reported using different medications, whether to treat psychosis, and immunomodulate, have been linked to the onset of catatonia (Bhangle et al., 2013;Lander et al., 2018;Durns et al., 2020). ...
This review aims to describe the clinical spectrum of catatonia, in order to carefully assess the involvement of astrocytes, neurons, oligodendrocytes, and microglia, and articulate the available preclinical and clinical evidence to achieve a translational understanding of the cellular and molecular mechanisms behind this disorder. Catatonia is highly common in psychiatric and acutely ill patients, with prevalence ranging from 7.6% to 38%. It is usually present in different psychiatric conditions such as mood and psychotic disorders; it is also a consequence of folate deficiency, autoimmunity, paraneoplastic disorders, and even autistic spectrum disorders. Few therapeutic options are available due to its complexity and poorly understood physiopathology. We briefly revisit the traditional treatments used in catatonia, such as antipsychotics, electroconvulsive therapy, and benzodiazepines, before assessing novel therapeutics which aim to modulate molecular pathways through different mechanisms, including NMDA antagonism and its allosteric modulation, and anti-inflammatory drugs to modulate microglia reaction and mitigate oxidative stress, such as lithium, vitamin B12, and NMDAr positive allosteric modulators.
... Astrocytes, similar to microglial cells, are involved in a wide spectrum of functions, including the provision of metabolic substrates to neurons for adequate synaptic activity, synthesis and recycling of neurotransmitters, diffusion of glutamate-induced excitatory signals [11][12][13], and interaction with endothelial cells of the bloodbrain barrier [14]. Indeed, since there is no direct contact between neurons and microvessels, some essential substrates (e.g., glucose and oxygen supplied by the cerebral circulation) are delivered to neurons by astrocytes [15]. ...
Aging induces substantial remodeling of glia, including density, morphology, cytokine expression, and phagocytic capacity. Alterations of glial cells, such as hypertrophy of lysosomes, endosomes and peroxisomes, and the progressive accumulation of lipofuscin, lipid droplets, and other debris have also been reported. These abnormalities have been associated with significant declines of microglial processes and reduced ability to survey the surrounding tissue, maintain synapses, and recover from injury. Similarly, aged astrocytes show reduced capacity to support metabolite transportation to neurons. In the setting of reduced glial activity, stressors and/or injury signals can trigger a coordinated action of microglia and astrocytes that may amplify neuroin-flammation and contribute to the release of neurotoxic factors. Oxidative stress and proteotoxic aggregates may burst astrocyte-mediated secretion of pro-inflammatory cytokines, thus activating microglia, favoring microgliosis, and ultimately making the brain more susceptible to injury and/or neurodegeneration. Here, we discuss the contribution of microglia and astrocyte oxidative stress to neuroinflammation and neurodegeneration, highlight the pathways that may help gain insights into their molecular mechanisms, and describe the benefits of antioxidant supplementation-based strategies.
... Anti-inflammatory cytokines may trigger neuroprotective astrocytes. The role of astrocytes in the initiation and progression of NDDs is widely accepted [39]. Postmortem studies on AD brains have demonstrated the presence of atrophic astrocytes and a close interaction between astrocytes and amyloid plaques, as well. ...
Neurodegenerative diseases (NDDs) are characterized by progressive deterioration of the structure and function of cells and their networks in the nervous system. There are currently no drugs or other treatments that can stop the progression of NDDs. NDDs have many similarities and common pathways, e.g., formation of misfolded amyloid proteins, intra- and extracellular amyloid deposits, and chronic inflammation. Initially, the inflammation process has a cytoprotective function; however, an elevated and prolonged immune response has damaging effects and causes cell death. Neuroinflammation has been a target of drug development for treating and curing NDDs. Treatment of different NDDs with non-steroid anti-inflammatory drugs (NSAIDs) has failed or has given inconsistent results. The use of NSAIDs in diagnosed Alzheimer’s disease is currently not recommended. Sigma-1 receptor (Sig-1R) is a novel target for NDD drug development. Sig-1R plays a key role in cellular stress signaling, and it regulates endoplasmic reticulum stress and unfolded protein response. Activation of Sig-1R provides neuroprotection in cell cultures and animal studies. Clinical trials demonstrated that several Sig-1R agonists (pridopidine, ANAVEX3-71, fluvoxamine, dextrometorphan) and their combinations have a neuroprotective effect and slow down the progression of distinct NDDs.
... Astrocytes are the most abundant cells in the human brain and serve as a bridge to build connections between neurons and cerebral microvessels [20,21]. In fact, astrocytes play important roles in maintaining the metabolic and ion homeostasis of neuronal cells, modulating synaptic transmission, and spreading glutamate-induced excitatory signals [22][23][24]. Because there is almost no direct contact between neurons and microvessels, some essential materials, such as glucose and oxygen supplied from the cerebral circulation, must interact with astroglia before reaching the neurons [25]. ...
An emerging concept termed the "neuro-glia-vascular unit" (NGVU) has been established in recent years to understand the complicated mechanism of multicellular interactions among vascular cells, glial cells, and neurons. It has been proverbially reported that the NGVU is significantly associated with neurodegenerative disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Physiological aging is an inevitable progression associated with oxidative damage, bioenergetic alterations, mitochondrial dysfunction, and neuroinflammation, which is partially similar to the pathology of AD. Thus, senescence is regarded as the background for the development of neurodegenerative diseases. With the exacerbation of global aging, senescence is an increasingly serious problem in the medical field. In this review, the coupling of each component, including neurons, glial cells, and vascular cells, in the NGVU is described in detail. Then, various mechanisms of age-dependent impairment in each part of the NGVU are discussed. Moreover, the potential bioenergetic alterations between different cell types in the NGVU are highlighted, which seems to be an emerging physiopathology associated with the aged brain. Bioenergetic intervention in the NGVU may be a new direction for studies on delaying or diminishing aging in the future.
... Channels for K + (voltage-independent, voltage-gated and Ca 2+ -dependent K + channels), Na + (voltage-gated, specific type of Na + channels regulated by extracellular Na + concentration and epithelial Na + channels), and Ca 2+ (voltage-gated, Orai, and Ca 2+ release channels), as well as for many other ions, have been registered (for a comprehensive review, refer to . Also, astrocytes express receptors for almost all neuroactive agents (Kettenmann and Zorec 2013;Verkhratsky 2010), including adenosine receptors (Dare et al. 2007;Pilitsis and Kimelberg 1998), purinoreceptors (Franke et al. 2001;Fumagalli et al. 2003;Verkhratsky et al. 2009), GABA receptors (MacVicar et al. 1989Nilsson et al. 1993), glycine receptors (Kirchhoff et al. 1996;Pastor et al. 1995), acetylcholine receptors (Graham et al. 2003;Sharma and Vijayaraghavan 2001), monoamines receptors (Hertz et al. 2010;Miyazaki et al. 2004;Shelton and McCarthy 2000), cannabinoid receptors (Navarrete and Araque 2008; Navarrete and Araque 2010), and both ionotropic and metabotropic glutamate receptors (Lalo et al. 2006;Sun et al. 2013;Verkhratsky and Butt 2013;Verkhratsky and Chvatal 2020). Lastly, numerous membrane transporter systems for different ions and neuroactive substances complete the complex astrocytic machinery required to exert their homeostatic function, such as the Na + -K + ATPase (Hertz et al. 2015), Ca 2+ -ATPases , as well as plasmalemmal transporters for GABA (Ribak et al. 1996), glycine (Zafra et al. 1995), glutamate (Verkhratsky and Rose 2020), glutamine (Scalise et al. 2016), and monocarboxylates (Halestrap 2012). ...
In the twentieth century, neuropsychiatric disorders have been perceived solely from a neurone-centric point of view, which considers neurones as the key cellular elements of pathological processes. This dogma has been challenged thanks to the better comprehension of the brain functioning, which, even if far from being complete, has revealed the complexity of interactions that exist between neurones and neuroglia. Glial cells represent a highly heterogeneous population of cells of neural (astroglia and oligodendroglia) and non-neural (microglia) origin populating the central nervous system. The variety of glia reflects the innumerable functions that glial cells perform to support functions of the nervous system. Aberrant execution of glial functions contributes to the development of neuropsychiatric pathologies. Arguably, all types of glial cells are implicated in the neuropathology; however, astrocytes have received particular attention in recent years because of their pleiotropic functions that make them decisive in maintaining cerebral homeostasis. This chapter describes the multiple roles of astrocytes in the healthy central nervous system and discusses the diversity of astroglial responses in neuropsychiatric disorders suggesting that targeting astrocytes may represent an effective therapeutic strategy.
... At the same time this potential promiscuity is very much restricted by the neurochemical environment in different parts of the CNS. Generally, astrocytes express receptors of the same modality as their neuronal neighbours; these modalities are congruent to the neurotransmitters released in a given brain region (Verkhratsky et al. 1998;Verkhratsky 2010). For example, in the spinal cord, where glycine is the main inhibitory neurotransmitter, astrocytes specifically express glycine receptors; in the basal ganglia, which utilise dopamine, astrocytes are endowed with dopamine receptors. ...
Astroglia are a diverse group of cells in the central nervous system. They are of the ectodermal, neuroepithelial origin and vary in morphology and function, yet, they can be collectively defined as cells having principle function to maintain homeostasis of the central nervous system at all levels of organisation, including homeostasis of ions, pH and neurotransmitters; supplying neurones with metabolic substrates; supporting oligodendrocytes and axons; regulating synaptogenesis, neurogenesis, and formation and maintenance of the blood-brain barrier; contributing to operation of the glymphatic system; and regulation of systemic homeostasis being central chemosensors for oxygen, CO2 and Na⁺. Their basic physiological features show a lack of electrical excitability (inapt to produce action potentials), but display instead a rather active excitability based on variations in cytosolic concentrations of Ca²⁺ and Na⁺. It is expression of neurotransmitter receptors, pumps and transporters at their plasmalemma, along with transports on the endoplasmic reticulum and mitochondria that exquisitely regulate the cytosolic levels of these ions, the fluctuation of which underlies most, if not all, astroglial homeostatic functions.
... BDNF has a central role in brain cell development due to its ability to protect brain cells from a wide variety of pathological conditions, including depression (Stadelmann et al., 2002). In addition to nerve cells, BDNF affects the number of glial cells (Sanyal et al., 2013), while the increase in the number of glial cells indicates a good nerve synapse function (Verkhratsky, 2010). ...
Introduction: Chronic stress exposure plays a role as a risk factor for depression. In chronic stress, there is prunning of nerve cell dendrites so that depression becomes irreversible. Depression is caused by low serotonin (5-HT2) neurotransmitters in the postsynaptic cleft. Recent findings in experimental animals indicate that serotonergic preparations are required to increase serotonin levels in the synapse opening, thereby triggering the formation of new dendrites to make depression reversible. The different results when these preparations create resistance in cases of chronic depression and actually increase the risk of uncomfortable and even fatal side effects with long-term use.
Methods: This Systematic Literature Review uses the PubMed and Google Scholar databases for the period 2015-2020. A total of 322 articles at the beginning of identification and those that met the inclusion criteria in this study were six articles.
Results: The results of data extraction showed that the depression condition caused by various stressors resulted in BDNF levels in the hippocampus decreased significantly by p≤0.005.
Conclusion: Based on the literature study, it was concluded that in depressive conditions, BDNF levels in the brain decreased.
... It is estimated that multiple neuronal cell somas, 300-600 dendrites and more than 100,000 synapses can be ensheathed by just a single cortical astrocyte in the mouse brain. The number is even larger in primates and humans, reaching 2 million synapses [81,82]. Hence, the concept of ʻtripartite synapses' (TS) was proposed, wherein astrocytes integrate process and exchange information with pre-and post-synaptic neuronal elements [83]. ...
Astrocytes are the most abundant glia in the central nervous system that play a significant role in disease. Recently, it roles of synaptic plasticity in neuropathological damages have been questioned whether the structural and functional plasticity of synapses contributes to the pathogenesis of Parkinson's disease. The regulation
of synaptic plasticity by astrocytes has also been widely researched based on astrocytes regulate synaptic plasticity by releasing Adenosine triphosphate, glutamate, and D-serine. We discuss the possible role of astrocytes in the regulation of synaptic plasticity, which may provide a new direction to Parkinson's disease treatment.
... The DUSP15 gene was shown to regulate myelination in oligodendrocytes and their differentiation and development [4]. Myelination control and axon support by oligodendrocytes are essential for the normal functions of complex neural cellular networks [5]. Pathology of oligodendrocytes has been correlated with ASD. ...
Objective:
Genetic factors play an important role in the development of autism spectrum disorder (ASD). This case-control study was to determine the association between childhood ASD and single nucleotide polymorphisms (SNPs) rs3746599 in the DUSP15 gene, rs7794745 in the CNTNAP2 gene, and rs251379 in the PCDHA gene in a Chinese Han population.
Methods:
Genotypes of SNPs were examined in DNA extracted from blood cells from 201 children with ASD and 200 healthy controls. The Children Autism Rating Scale (CARS) was applied to evaluate the severity of the disease and language impairment. The relationship between SNPs and the risk of ASD or the severity of the disease was determined by logistic regression and one-way ANOVA.
Results:
The genotype G/G of rs3746599 in the DUSP15 gene was significantly associated with a decreased risk of ASD (odds ratio (OR) = 0.65, 95% confidence interval (CI): 0.42-0.99, P = 0.0449). The T allele of rs7794745 in the CNTNAP2 gene was associated with an increased risk of ASD (OR = 1.34, 95% CI: 1.01-1.77, P = 0.0435). The SNP rs251379 was not associated with ASD. Though none of the SNPs examined were associated with ASD severity, rs7794745 was associated with severity of language impairment.
Conclusions:
Our findings suggest that both rs3746599 in the DUSP15 gene and rs7794745 in the CNTNAP2 gene are associated with risk of childhood ASD, and rs7794745 is also related to the severity of language impairment in autistic children from a Chinese Han population.
... Astrocytes perform a wide variety of critical functions determining normal operation of the nervous tissue. Numerous receptors expressed in astrocytes allow them to sense neuronal activity (Verkhratsky 2010), activation of these receptors trigger astrocytic ionic signalling, mainly mediated by changes in cytosolic concentration of Ca 2+ and Na + (Rose and Verkhratsky 2016), which control a multitude of plasmalemmal "homeostatic" transporters (Verkhratsky and Rose 2020). These transporters are responsible for K + buffering, clearance of neurotransmitters including glutamate, ATP, GABA, adenosine and endocannabinoids among others, maintaining synaptic transmission, preventing excitotoxicity and providing for neuroprotection (Vasile, Dossi, and Rouach 2017;Verkhratsky and Nedergaard 2018). ...
Astrocytes perform a wide variety of essential functions defining normal operation of the nervous system, and are active contributors to the pathogenesis of neurodegenerative disorders such as Alzheimer among others. Recent data provide compelling evidence that distinct reactive astrocyte states are associated with specific stages of Alzheimer´s disease. The advent of transcriptomics technologies enables rapid progress in the characterisation of such pathological astrocyte states. In this review, we provide an overview of the origin, main functions, molecular and morphological features of astrocytes in physiological as well as pathological conditions related to Alzheimer´s disease. We will also explore the main roles of astrocytes in the pathogenesis of Alzheimer´s disease and summarize main transcriptional changes and altered molecular pathways observed in astrocytes during the course of the disease.
... In this way, Ca 2+ levels are influenced as well. In line with this observation, in control conditions, glutamate can induce a slight but significant increase in both cytosolic and mitochondrial Ca 2+ levels ( Figure 5), consistently with our previous findings [38,41] and as already proposed in astrocytes [87,88]. The latter event activates the mitochondrial Ca 2+ sensitive dehydrogenases, driving glutamate utilization and enhancing ATP synthesis [50]. ...
Increasing evidence suggests that metabolic alterations may be etiologically linked to neurodegenerative disorders such as Parkinson's disease (PD) and in particular empathizes the possibility of targeting mitochondrial dysfunctions to improve PD progression. Under different pathological conditions (i.e., cardiac and neuronal ischemia/reperfusion injury), we showed that supplementation of energetic substrates like glutamate exerts a protective role by preserving mitochondrial functions and enhancing ATP synthesis through a mechanism involving the Na+-dependent excitatory amino acid transporters (EAATs) and the Na+/Ca2+ exchanger (NCX). In this study, we investigated whether a similar approach aimed at promoting glutamate metabolism would be also beneficial against cell damage in an in vitro PD-like model. In retinoic acid (RA)-differentiated SH-SY5Y cells challenged with α-synuclein (α-syn) plus rotenone (Rot), glutamate significantly improved cell viability by increasing ATP levels, reducing oxidative damage and cytosolic and mitochondrial Ca2+ overload. Glutamate benefits were strikingly lost when either EAAT3 or NCX1 expression was knocked down by RNA silencing. Overall, our results open the possibility of targeting EAAT3/NCX1 functions to limit PD pathology by simultaneously favoring glutamate uptake and metabolic use in dopaminergic neurons.
... 80 The highly branched neuroglial cells that are located between neurons have intimate functional relationships with the neurons, providing both mechanical and physiological support. 81,82 CNS diseases are a type of neurological disorders caused by various factors including trauma, infections, degeneration, autoimmune diseases and stroke, and can alter and degrade the function or structure of cells and tissues in the CNS. 83,84 In particular, the age-dependent neurodegenerative diseases represent a major disease in human because the elderly population has increased in recent years. ...
Drivers of RNA interference are potent for manipulating gene and protein levels, which enable the restoration of dysregulated mRNA expression that is commonly associated with injuries and diseases. This review summarizes the potential of targeting neuroglial cells, using RNA interference, to treat nerve injuries sustained in the central nervous system. In addition, the various methods of delivering these RNA interference effectors will be discussed.
... Sodium influx in astrocytes is mediated by plasmalemmal channels and Na + -dependent solute carrier transporters (Fig. 1). Depending on the brain region, astrocytes may express several types of ionotropic receptors including N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) type glutamate receptors, P2X purinoceptors and nicotinic acetylcholine receptors (Verkhratsky, 2010;Verkhratsky & Nedergaard, 2018). Although some of these receptors exhibit a Ca 2+ permeability, their current is carried mainly by Na + , which dominates the ionic composition of the extracellular milieu. ...
... Oxidative stress is one of the major mechanisms implicated in MeHg-induced CNS injury (Farina and Aschner, 2017). As an electrophile with high affinity for thiol (-SH) and/or selenol (-SeH) groups of endogenous molecules (Verkhratsky, 2010), MeHg can disrupt key cellular antioxidants and thereby impair antioxidant capacity. In addition, MeHg triggers the formation of reactive oxygen species (ROS), which further accelerates the MeHg-induced imbalance in redox homeostasis. ...
... This membrane hyperactivity could be related to pro-inflammatory mediators, such as cytokines, reactive oxygen species and free radicals to name a few, released from the activated astrocytes and glial cells, which themselves have been shown to be altered morphologically Rodriguez et al. 2010). Astrocytes regulate the microenvironment by providing K + ion homeostasis for excitable membranes, and their reduced function could lead to an accumulation of extracellular K + released from neurons (Verkhratsky 2010), resulting in a more depolarized membrane potential, rendering cells more excitable. These hyperactive membrane properties become weak and diminished with age, which is probably due alterations and down regulation of leak conductance responsible for generating the intrinsic firing of these cells. ...
Synaptic dysfunction is widely proposed as an initial insult leading to the neurodegeneration observed in Alzheimer's disease (AD). We hypothesize that the initial insult originates in the lateral entorhinal cortex (LEC) due to deficits in key interneuronal functions and synaptic signaling mechanisms, in particular, Wnt (Wingless/integrated). To investigate this hypothesis, we utilized the first knock-in mouse model of AD (AppNL-F/NL-F), expressing a mutant form of human amyloid-β (Aβ) precursor protein. This model shows an age-dependent accumulation of Aβ, neuroinflammation, and neurodegeneration. Prior to the typical AD pathology, we showed a decrease in canonical Wnt signaling activity first affecting the LEC in combination with synaptic hyperexcitation and severely disrupted excitatory-inhibitory inputs onto principal cells. This synaptic imbalance was consistent with a reduction in the number of parvalbumin-containing (PV) interneurons, and a reduction in the somatic inhibitory axon terminals in the LEC compared with other cortical regions. However, targeting GABAA receptors on PV cells using allosteric modulators, diazepam, zolpidem, or a nonbenzodiazepine, L-838,417 (modulator of α2/3 subunit-containing GABAA receptors), restored the excitatory-inhibitory imbalance observed at principal cells in the LEC. These data support our hypothesis, providing a rationale for targeting the synaptic imbalance in the LEC for early stage therapeutic intervention to prevent neurodegeneration in AD.
... Operation of this metabotropic pathway has been described and characterised in astrocytes in vitro, in situ and in vivo; with a particular role played by InsP 3 receptor type II [47][48][49][50][51][52][53][54][55][56]. All in all these experiments have unequivocally demonstrated that astrocytes potentially (i.e in vitro) can express all types of receptors to neurotransmitters, neuromodulators and neurohormones present in the CNS; this expression however is tightly regulated and restricted in vivo [10,14,57]. It appeared that the modality of astroglial neurotransmitter receptors is controlled by their immediate neurochemical environment and generally matches the modality of receptors present in their neuronal neighbours. ...
Astrocytes support glutamatergic neurotransmission in the central nervous system through multiple mechanisms which include: (i) glutamate clearance and control over glutamate spillover due to operation of glutamate transporters; (ii) supply of obligatory glutamate precursor glutamine via operation of glutamate–glutamine shuttle; (iii) supply of l-serine, the indispensable precursor of positive NMDA receptors neuromodulator d-serine and (iv) through overall homoeostatic control of the synaptic cleft. Astroglial cells express an extended complement of ionotropic and metabotropic glutamate receptors, which mediate glutamatergic input to astrocytes. In particular a sub-population of astrocytes in the cortex and in the spinal cord express specific type of NMDA receptors assembled from two GluN1, one GluN2C or D and one GluN3 subunits. This composition underlies low Mg²⁺ sensitivity thus making astroglial NMDA receptors operational at resting membrane potential. These NMDA receptors generate ionic signals in astrocytes and are linked to several astroglial homoeostatic molecular cascades.
... Sodium influx in astrocytes is mediated by plasmalemmal channels and Na + -dependent solute carrier transporters (Fig. 1). Depending on the brain region, astrocytes may express several types of ionotropic receptors including N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) type glutamate receptors, P2X purinoceptors and nicotinic acetylcholine receptors (Verkhratsky, 2010;Verkhratsky & Nedergaard, 2018). Although some of these receptors exhibit a Ca 2+ permeability, their current is carried mainly by Na + , which dominates the ionic composition of the extracellular milieu. ...
Astrocytes are homeostatic and protective cells of the central nervous system. Astroglial homeostatic responses are tightly coordinated with neuronal activity. Astrocytes maintain neuronal excitability through regulation of extracellular ion concentrations, as well as assisting and modulating synaptic transmission by uptake and catabolism of major neurotransmitters. Moreover, they support neuronal metabolism and detoxify ammonium and reactive oxygen species. Astroglial homeostatic actions are initiated and controlled by intercellular signalling of ions, including Ca²⁺, Na⁺, Cl⁻, H⁺ and possibly K⁺. This review summarises current knowledge on ionic signals mediated by the major monovalent ions, which occur in microdomains, as global events, or as propagating intercellular waves and thereby represent the substrate for astroglial excitability. image
... In the formation of brain-like constructs a pivotal role in the survival and differentiation of neurons is played by glial cells [65]. In order to highlight the morphology of glia cells, fixed 3D and 2D cultures were exposed to GFAP primary antibody followed by secondary antibody Alexa Fluor 549. ...
... Further evidence of the requirement of astrocytes in proper glucose sensing comes from studies using knock out models for connexins. Astrocytes are tightly connected by gap junctions to form a large functional syncytium that allows the selective transmission of nutrients and signaling molecules over long distances [35]. Connexins form hemi-channels that are instrumental for astrocytic network transmission. ...
Astrocytes have historically been considered structural supporting cells for neurons. Thanks to new molecular tools, allowing specific cell ablation or over-expression of genes, new unexpected astrocytic functions have recently been unveiled. This review focus on emerging groundbreaking findings showing that hypothalamic astrocytes are pivotal for the regulation of whole body energy homeostasis. Hypothalamic astrocytes sense glucose and fatty acids, and express receptors for several peripheral hormones such as leptin and insulin. Furthermore, they display striking sexual dimorphism which may account, at least partially, for gender specific differences in energy homeostasis. Metabolic alterations have been shown to influence the initiation and progression of many neurodegenerative disorders. A better understanding of the roles and interplay between the different brain cells in regulating energy homeostasis could help develop new therapeutic strategies to prevent or cure neurodegenerative disorders.
... ischemia medication, the primary aim of the present study was to elucidate the role of p38 MAPK played in the sulbactaminduced neuronal protection and GLT-1 up-regulation against ischemia. It might be difficult in vivo study to discern whether the up-regulation of GLT-1 after sulbactam treatment was directly mediated by p38 MAPK activation in astrocytes because activity of astrocytes may be influenced by neurons in some extent (Verkhratsky, 2010;Barreto et al., 2011;Parpura et al., 2012). Therefore, the present study was performed using neuron-astrocyte co-cultures for neuronal protective experiments and using astrocyte cultures for experiments on GLT-1 expression. ...
Sulbactam is an atypical β-lactam medication and reported to be neuroprotective by up-regulating glial glutamate transporter-1 (GLT-1) in rats. The present study was undertaken to study the role of p38 MAPK signal pathway in sulbactam induced up-regulation of GLT-1 expression in astrocytes and anti-ischemic effect. Neuron-astrocyte co-cultures and astrocyte cultures from neonatal Wistar rats were used. Cerebral ischemia was mimicked by oxygen-glucose deprivation (OGD). Hoechst (HO)/propidium iodide (PI) double fluorescence staining and 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide assay were used to evaluate neuronal death and cell viability, respectively. Immunocytochemistry and Western blot were used to detect protein expressions. Sulbactam pre-incubation significantly and dose-dependently prevented neuronal death and decline in cell viability induced by OGD in neuron-astrocyte co-cultures, and upregulated GLT-1 expression in astrocyte cultures endured OGD, which suggested that sulbactam might protect neurons against OGD by up-regulating astrocytic GLT-1 expression. It was further shown that the phosphorylated-p38 MAPK expression in astrocytes was up-regulated after the sulbactam pre-incubation and this up-regulation was moderate in amplitude. Especially, the time course of the up-regulation of phosphorylated-p38 MAPK was obviously earlier than that of GLT-1, which suggested possibility that p38 MAPK might be an upstream signal for GLT-1 up-regulation induced by sulbactam. We further found that SB203580, the specific inhibitor of p38 MAPK, dose-dependently inhibited the GLT-1 up-regulation induced by sulbactam either in non- or OGD-treated astrocytes and the protective effect of sulbactam on co-cultured neurons against OGD. Taken together, it might be concluded that sulbactam protects cerebral neurons against OGD by up-regulating astrocytic GLT-1 expression via p38 MAPK signal pathway.
... Astrocytes perform various important functions in the brain and occupy a larger portion than neurons. Astrocytes play an active role in the neuron-neuroglia crosstalk, maintaining metabolic and ion homeostasis in neurons (Verkhratsky, 2010). In addition, astrocytes modulate the growth, signal regulation, and synaptic plasticity of neurons. ...
Brain aging induces neuropsychological changes, such as decreased memory capacity, language ability, and attention; and is also associated with neurodegenerative diseases. However, most of the studies on brain aging are focused on neurons, while senescence in astrocytes has received less attention. Astrocytes constitute the majority of cell types in the brain and perform various functions in the brain such as supporting brain structures, regulating blood-brain barrier permeability, transmitter uptake and regulation, and immunity modulation. Recent studies have shown that SIRT1 and SIRT2 play certain roles in cellular senescence in peripheral systems. Both SIRT1 and SIRT2 inhibitors delay tumor growth in vivo without significant general toxicity. In this study, we investigated the role of tenovin-1, an inhibitor of SIRT1 and SIRT2, on rat primary astrocytes where we observed senescence and other functional changes. Cellular senescence usually is characterized by irreversible cell cycle arrest and induces senescence-associated β-galactosidase (SA-β-gal) activity. Tenovin-1-treated astrocytes showed increased SA-β-gal-positive cell number, senescence-associated secretory phenotypes, including IL-6 and IL-1β, and cell cycle-related proteins like phospho-histone H3 and CDK2. Along with the molecular changes, tenovin-1 impaired the wound-healing activity of cultured primary astrocytes. These data suggest that tenovin-1 can induce cellular senescence in astrocytes possibly by inhibiting SIRT1 and SIRT2, which may play particular roles in brain aging and neurodegenerative conditions.
... Nonetheless astrocytes express an extended compliment of "excitable" molecules and mechanisms which include plasmalemmal ion channels and receptors to neurotransmitters, neuromodulators and neurohormones, cytoplasmic structures that generate transient elevations in cytosolic levels of second messengers, including [Ca 2+ ] i and cyclic adenosine monophosphate ([cAMP] i ) (see Horvat and Vardjan, this special issue [21] and [67,68,76,89]). Expression of these receptors and channels varies depending on the brain region; in particular astroglial receptors are, as a rule, congruent to the major neurotransmitters released in their vicinity [69,78]. Stimulation of astroglial receptors with appropriate signalling molecules triggers fluctuations in the intracellular ion concentrations, providing a substrate for excitability of astrocytes. ...
Astroglia, a heterogeneous type of neuroglia, play key homeostatic functions in the central nervous system (CNS) and represent an important defence system. Impaired homeostatic capacity of astrocytes manifests in diseases and this is mirrored in various astrocyte-based pathological features including reactive astrogliosis, astrodegeneration with astroglial atrophy and pathological remodelling of astrocytes. All of these manifestations are most prominently associated with infectious insults, mediated by bacteria, protozoa and viruses. Here we focus into neurotropic viruses such as tick-borne encephalitis (TBEV) and Zika virus (ZIKV), both belonging to Flaviviridae and both causing severe neurological impairments. We argue that astrocytes provide a route through which neurotropic infectious agents attack the CNS, since they are anatomically associated with the blood-brain barrier and exhibit aerobic glycolysis, a metabolic specialization of highly morphologically dynamic cells, which may provide a suitable metabolic milieu for proliferation of infectious agents, including viral bodies.
... Nonetheless astrocytes express an extended compliment of "excitable" molecules and mechanisms which include plasmalemmal ion channels and receptors to neurotransmitters, neuromodulators and neurohormones, cytoplasmic structures that generate transient elevations in cytosolic levels of second messengers, including [Ca 2+ ] i and cyclic adenosine monophosphate ([cAMP] i ) (see Horvat and Vardjan, this special issue [21] and [67,68,76,89]). Expression of these receptors and channels varies depending on the brain region; in particular astroglial receptors are, as a rule, congruent to the major neurotransmitters released in their vicinity [69,78]. Stimulation of astroglial receptors with appropriate signalling molecules triggers fluctuations in the intracellular ion concentrations, providing a substrate for excitability of astrocytes. ...
Astrocytes, the neural homeostatic cells, play a key role in the information processing in the central nervous system. They express multiple receptors which respond to a number of chemical messengers and get excited as evidenced by an increase in second messengers in short and delayed time domains. Astrocytes secrete numerous neuroactive agents and mount various homeostatic responses. These signal integrating functions are key factors of neuropathology (better termed astroneuropathology): they provide for neuroprotection through both homeostatic support and astroglial reactivity; failure in astroglial defensive or supporting capabilities facilitates evolution of neurological disorders.
The phospholipid and free fatty acid (FFA) composition of neuronal membranes plays a crucial role in learning and memory, but the mechanisms through which neuronal activity affects the brain’s lipid landscape remain largely unexplored. The levels of saturated FFAs, particularly of myristic acid (C14:0), strongly increase during neuronal stimulation and memory acquisition, suggesting the involvement of phospholipase A1 (PLA1) activity in synaptic plasticity. Here, we show that genetic ablation of the PLA1 isoform DDHD2 in mice dramatically reduces saturated FFA responses to memory acquisition across the brain. Furthermore, DDHD2 loss also decreases memory performance in reward-based learning and spatial memory models prior to the development of neuromuscular deficits that mirror human spastic paraplegia. Via pulldown-mass spectrometry analyses, we find that DDHD2 binds to the key synaptic protein STXBP1. Using STXBP1/2 knockout neurosecretory cells and a haploinsufficient STXBP1 +/− mouse model of human early infantile encephalopathy associated with intellectual disability and motor dysfunction, we show that STXBP1 controls targeting of DDHD2 to the plasma membrane and generation of saturated FFAs in the brain. These findings suggest key roles for DDHD2 and STXBP1 in lipid metabolism and in the processes of synaptic plasticity, learning, and memory.
Multiple sclerosis is a chronic neurological disease characterized by inflammation and degeneration within the central nervous system. Over the course of the disease, most MS patients successively accumulate inflammatory lesions, axonal damage, and diffuse CNS pathology, along with an increasing degree of motor disability. While the pharmacological approach to MS targets inflammation to decrease relapse rates and relieve symptoms, disease-modifying therapy and immunosuppressive medications may not prevent the accumulation of pathology in most patients leading to long-term motor disability. This has been met with recent interest in promoting plasticity-guided concepts, enhanced by neurophysiological and neuroimaging approaches to address the preservation of motor function.
Since the discovery of purinergic signaling in the 1960s, many researchers focused on the central nervous system neurotransmission. Some neurons present high permeability to Ca2+ upon ATP challenge. Here, in this chapter, we highlight some of the most relevant findings regarding communication in the brain through P1 adenosine receptors or P2 purine receptors. Glial cells may regulate synaptic transmission and modulate neuronal activity by releasing neuroactive substances including ATP. Conversely, ATP may act at glial P2 receptors influencing glial functions. The role of ATP as gliotransmitter involved in the control of neuronal or neuroglial circuits will be discussed in this chapter.KeywordsAdenosine Extracellular ATP Neuron Astrocytes Microglia Neural communication
A retrospective analysis of views on the regulation of the «sleep-wakefulness» cycle from the reticular theory of sleep to the Saper's model was carried out. A modified version of the Saper's trigger made it possible to use the results of a comparative analysis of drugs used in the treatment of sleep disorders to develop new, comprehensive, effective approaches to the pharmacotherapy of the most common sleep disorders. It seems that this approach will be useful in the development of effective pharmacotherapy for sleep disorders.
Astrocytes are key cells in the central nervous system. They are involved in many important functions under physiological and pathological conditions. As part of neuroglia, they have been recognised as cellular elements in their own right. The name astrocyte was first proposed by Mihaly von Lenhossek in 1895 because of the finely branched processes and star-like appearance of these particular cells. As early as the late 19th and early 20th centuries, Ramon y Cajal and Camillo Golgi had noted that although astrocytes have stellate features, their morphology is extremely diverse. Modern research has confirmed the morphological diversity of astrocytes both in vitro and in vivo and their complex, specific, and important roles in the central nervous system. In this review, the functions of astrocytes and their roles are described.
Cortical state, defined by population-level neuronal activity patterns, determines sensory perception. While arousal-associated neuromodulators—including norepinephrine (NE)—reduce cortical synchrony, how the cortex resynchronizes remains unknown. Furthermore, general mechanisms regulating cortical synchrony in the wake state are poorly understood. Using in vivo imaging and electrophysiology in mouse visual cortex, we describe a critical role for cortical astrocytes in circuit resynchronization. We characterize astrocytes’ calcium responses to changes in behavioral arousal and NE, and show that astrocytes signal when arousal-driven neuronal activity is reduced and bi-hemispheric cortical synchrony is increased. Using in vivo pharmacology, we uncover a paradoxical, synchronizing response to Adra1a receptor stimulation. We reconcile these results by demonstrating that astrocyte-specific deletion of Adra1a enhances arousal-driven neuronal activity, while impairing arousal-related cortical synchrony. Our findings demonstrate that astrocytic NE signaling acts as a distinct neuromodulatory pathway, regulating cortical state and linking arousal-associated desynchrony to cortical circuit resynchronization.
Glia, which was formerly considered to exist just to connect neurons, now plays a key function in a wide range of physiological events, including formation of memory, learning, neuroplasticity, synaptic plasticity, energy consumption, and homeostasis of ions. Glial cells regulate the brain's immune responses and confers nutritional and structural aid to neurons, making them an important player in a broad range of neurological disorders. Alzheimer's, ALS, Parkinson's, frontotemporal dementia (FTD), and epilepsy are a few of the neurodegenerative diseases that have been linked to microglia and astroglia cells, in particular. Synapse growth is aided by glial cell activity, and this activity has an effect on neuronal signalling. Each glial malfunction in diverse neurodegenerative diseases is distinct, and we will discuss its significance in the progression of the illness, as well as its potential for future treatment.
Writing involves the transformation of ideas, emotions and sounds into graphic form. Ideagrams help clarify complex ideas and can be considered to be forms of stored memory. The emergence of chemistry from alchemy involved the adaptation of graphic notations to comprehend the invisible atomic and molecular structures of complex matter, and to spread and store that knowledge. This culminated in the molecular representations of chemical reactions and chemical compounds such as natural products, sugars, polymers, proteins and metal complexes. We review the development of textual and graphic notations of chemical structures from circa‐1700 to now. We present a Timeline that graphically summarizes the salient stages in the evolution of chemical notations (“chemography”) from alchemy, leading to modern “psycho‐chemistry”. The Timeline correlates the emergence of new chemical notations with crucial technological inventions.
There is a need for an genomic theoretical framework which would allow for phenomena observed in cell and also explain evolution of cellular life. The search for a genomic explanation to cancer lead to the concept of the genomic script which extends its influence over the workings of genome of a normal cell too. This framework explains multiple phenomenon like the development of an embryo, differentiation of cells, and genomic workings of cancer. It also explains the evolution of unicellular and multicellular organisms. Yet it remains a simple construct; a perennial loop with adaptor loops constituting the genomic script.
There is a need for a genomic theoretical framework which would explain the increasingly vast and discreet genomic data in the context of phenomena observed in cell. The search for a genomic explanation to functional networks of cancer metasignature genes lead to the concept of the genomic script which extends its influence over the workings of genome in general. This framework explains multiple phenomenon like the development of an embryo, differentiation of cells, and genomic workings of cancer. It also shines light on the evolution of unicellular and multicellular organisms. Yet it remains a simple construct; a perennial loop with its adaptor loops constituting the genomic script.
There is a need for an genomic theoretical framework which would allow for phenomena observed in cell and also explain evolution of cellular life. The search for a genomic explanation to cancer lead to the concept of the genomic script which extends its influence over the workings of genome of a normal cell too. This framework explains multiple phenomenon like the development of an embryo, differentiation of cells, and genomic workings of cancer. It also explains the evolution of unicellular and multicellular organisms. Yet it remains a simple construct; a perennial loop with adaptor loops constituting the genomic script.
Background
Astrocytes are the main cellular constituent in the central nervous system. Astrocyte cultures from rodent brains are most commonly used in the experimental practice. However, important differences between rodent and human astrocytes exist. The aim of this study was to develop an improved protocol for routine preparation of primary astrocyte culture from adult human brain, obtained after trauma.
New Method
Tissue obtained during neurotrauma operation was mechanically decomposed and centrifuged. The cell sediment was resuspended in cell culture medium, plated in T25 tissue flasks and incubated for one month at 37 °C in 5 % CO2. The medium was replaced twice weekly and microglia were removed. Once confluent, the purity of cultures was assessed. The culture was characterised immunocytochemically for specific astrocytic markers (GFAP, GLAST and S100B). Cell morphology was examined through the actin cytoskeleton labelling with fluorescent phalloidin.
Results
Under basal conditions, adult astrocytes exhibited astrocyte-specific morphology and expressed specific markers. Approximately 95 % of cells were positive for the main glial markers (GFAP, GLAST, S100B).
Comparison with Existing Method
We established an easy and cost-effective method for a highly enriched primary astrocyte culture from adult human brain.
Conclusion
The isolation technique provides sufficient quantities of isolated cells. The culture obtained in this study exhibits the biochemical and physiological properties of astrocytes. It may be useful for elucidating the mechanisms related to the adult brain, exploring changes between neonatal and adult astrocytes, novel therapeutic targets, cell therapy experiments, as well as investigating compounds involved in cytotoxicity and cytoprotection.
Astrocytes, a type of neuroglia, are heterogeneous cells, forming (together with oligodendrocytes and microglia) the gliocrine system, involved in maintaining homoeostatic balance in the brain. Gliocrine neuroglia operate as a secretory network which provides for humoural signalling in the brain and in the spinal cord. In this chapter, we first describe astroglial functions in health and disease and focus on the mechanisms of cytoplasmic ionic excitability. Then, we discuss responses of astroglia to pathological states and introduce the gliocrine secretory mechanisms and molecules released from astrocytes. Finally, we describe the physiology of vesicle-based secretion and conclude that vesicular mechanisms, previously considered to be an exclusive property of neurons in the brain, play an elaborated role in astroglial (patho)physiology, thus representing a basis for development of new neurological therapies aimed at astrocytes.
It is well established that mitochondria are the main source of ATP production within cells. However, mitochondria have other remarkable functions, serving as important modulators of cellular Ca2+ signaling, and it is now generally recognized that control over Ca2+ homeostasis is intrinsically interwoven with mitochondrial abilities to adjust and tune ATP production. In this review, we describe the mechanisms that mitochondria use to balance Ca2+ homeostasis maintenance and cell energy metabolism. In recent years, the knowledge on the molecular machinery mediating Ca2+ influx/efflux has been improved and, albeit still open to further investigations, several lines of evidence converge on the hypothesis that plasma membrane Na+/Ca2+ exchanger (NCX) isoforms are also expressed at the mitochondrial level, where they contribute to the Ca2+ and Na+ homeostasis maintenance. In particular, the connection between mitochondrial NCX activity and metabolic substrates utilization is further discussed here. We also briefly focus on the alterations of both mitochondrial Ca2+ handling and cellular bioenergetics in neurodegenerative diseases, such as Parkinson's and Alzheimer's disease.
Astrocyte glutamate release can modulate synaptic activity and participate in brain intercellular signaling. P2X7 receptors form large ion channels when activated by ATP or other ligands. Here we show that P2X7 receptors provide a route for excitatory amino acid release from astrocytes. Studies were performed using murine cortical astrocyte cultures. ATP produced an inward current in patch-clamped astrocytes with properties characteristic of P2X7 receptor activation: the current was amplified in low divalent cation medium, blocked by pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid (PPADS), and more potently activated by 3'-O-(4-benzoyl)benzoyl ATP (BzATP) than by ATP itself. Measurement of current reversal potentials showed the relative BzATP-induced permeabilities to different substrates to be Na+, 1 > Cl-, 0.34 > N-methyl-D-glucamine, 0.27 > L-glutamate, 0.15 approximately D-aspartate, 0.16. Astrocytes exposed to BzATP also became permeable to Lucifer yellow, indicating a large channel opening. Release of L-glutamate and D-aspartate through P2X7 channels was confirmed using radiolabeled tracers. As with the inward current, release of glutamate and D-aspartate was induced by BzATP more potently than ATP, amplified in Ca2+/Mg2+-free medium, and blocked by PPADS or oxidized ATP. Efflux through P2X7 channels is a previously unrecognized route of ligand-stimulated, nonvesicular astrocyte glutamate release.
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 have generated transgenic mice in which astrocytes are labeled by the enhanced green fluorescent protein (EGFP) under the control of the human glial fibrillary acidic protein (GFAP) promoter. In all regions of the CNS, such as cortex, cerebellum, striatum, corpus callosum, hippocampus, retina, and spinal cord, EGFP-positive cells with morphological properties of astrocytes could be readily visualized by direct fluorescence microscopy in living brain slices or whole mounts. Also in the PNS, nonmyelinating Schwann cells from the sciatic nerve could be identified by their bright green fluorescence. Highest EGFP expression was found in the cerebellum. Already in acutely prepared whole brain, the cerebellum appeared green-yellowish under normal daylight. Colabeling with GFAP antibodies revealed an overlap with EGFP in the majority of cells. Some brain areas, however, such as retina or hypothalamus, showed only low levels of EGFP expression, although the astrocytes were rich in GFAP. In contrast, some areas that were poor in immunoreactive GFAP were conspicuous for their EGFP expression. Applying the patch clamp technique in brain slices, EGFP-positive cells exhibited two types of membrane properties, a passive membrane conductance as described for astrocytes and voltage-gated channels as described for glial precursor cells. Electron microscopical investigation of ultrastructural properties revealed EGFP-positive cells enwrapping synapses by their fine membrane processes. EGFP-positive cells were negative for oligodendrocyte (MAG) and neuronal markers (NeuN). As response to injury, i.e., by cortical stab wounds, enhanced levels of EGFP expression delineated the lesion site and could thus be used as a live marker for pathology. GLIA 33:72–86, 2001. © 2000 Wiley-Liss, Inc.
Upon central nervous system injury, the extracellular concentrations of nucleotides and cysteinyl-leukotrienes, two unrelated families of endogenous signalling molecules, are markedly increased at the site of damage, suggesting that they may act as 'danger signals' to alert responses to tissue damage and start repair. Here we show that, in non-injured spinal cord parenchyma, GPR17, a P2Y-like receptor responding to both uracil nucleotides (e.g. UDP-glucose) and cysteinyl-leukotrienes (e.g. LTD4 and LTC4), is present on a subset of neurons and of oligodendrocytes at different stages of maturation, whereas it is not expressed by astrocytes. GPR17 immunoreactivity was also found on ependymal cells lining the central canal that still retain some of the characteristics of stem/progenitor cells during adulthood. Induction of spinal cord injury (SCI) by acute compression resulted in marked cell death of GPR17+ neurons and oligodendrocytes inside the lesion followed by the appearance of proliferating GPR17+ microglia/macrophages migrating to and infiltrating into the lesioned area. Moreover, 72 h after SCI, GPR17+ ependymal cells started to proliferate and to express GFAP, suggesting their activation and 'de-differentiation' to pluripotent progenitor cells. The in vivo knock down of GPR17 by an antisense oligonucleotide strategy during SCI induction markedly reduced tissue damage and related histological and motor deficits, thus confirming the crucial role played by this receptor in the early phases of tissue damage development. Taken together, our findings suggest a dual and spatiotemporal-dependent role for GPR17 in SCI. At very early times after injury, GPR17 mediates neuronal and oligodendrocyte death inside the lesioned area. At later times, GPR17+ microglia/macrophages are recruited from distal parenchymal areas and move toward the lesioned zone, to suggest a role in orchestrating local remodelling responses. At the same time, the induction of the stem cell marker GFAP in GPR17+ ependymal cells suggests initiation of repair mechanisms. Thus, GPR17 may act as a 'sensor' of damage that is activated by nucleotides and cysteinyl-leukotrienes released in the lesioned area, and could also participate in post-injury responses. Moreover, its presence on spinal cord pre-oligodendrocytes and precursor-like cells suggests GPR17 as a novel target for therapeutic manipulation to foster remyelination and functional repair in SCI.
Purinergic transmission is one of the most ancient and widespread extracellular signalling systems. In the brain, purinergic signalling plays a unique role in integrating neuronal and glial cellular circuits, as virtually every type of glial cell possesses receptors to purines and pyrimidines. These receptors, represented by metabotropic P1 adenosine receptors, metabotropic P2Y purinoceptors and ionotropic P2X purinoceptors, control numerous physiological functions of glial cells and are intimately involved in virtually every form of neuropathology. In this essay, we provide an in depth overview of purinoceptor distribution in two types of CNS glia—in astrocytes and oligodendrocytes—and discuss their physiological and pathophysiological roles.
Purinergic transmission is one of the most ancient and widespread extracellular signalling systems. In the brain, purinergic signalling plays a unique role in integrating neuronal and glial cellular circuits, as virtually every type of glial cell possesses receptors to purines and pyrimidines. These receptors, represented by metabotropic P1 adenosine receptors, metabotropic P2Y purinoceptors and ionotropic P2X purinoceptors, control numerous physiological functions of glial cells and are intimately involved in virtually every form of neuropathology. In this essay, we provide an in depth overview of purinoceptor distribution in two types of CNS glia--in astrocytes and oligodendrocytes--and discuss their physiological and pathophysiological roles.
Defining the microanatomic differences between the human brain and that of other mammals is key to understanding its unique computational power. Although much effort has been devoted to comparative studies of neurons, astrocytes have received far less attention. We report here that protoplasmic astrocytes in human neocortex are 2.6-fold larger in diameter and extend 10-fold more GFAP (glial fibrillary acidic protein)-positive primary processes than their rodent counterparts. In cortical slices prepared from acutely resected surgical tissue, protoplasmic astrocytes propagate Ca(2+) waves with a speed of 36 microm/s, approximately fourfold faster than rodent. Human astrocytes also transiently increase cystosolic Ca(2+) in response to glutamatergic and purinergic receptor agonists. The human neocortex also harbors several anatomically defined subclasses of astrocytes not represented in rodents. These include a population of astrocytes that reside in layers 5-6 and extend long fibers characterized by regularly spaced varicosities. Another specialized type of astrocyte, the interlaminar astrocyte, abundantly populates the superficial cortical layers and extends long processes without varicosities to cortical layers 3 and 4. Human fibrous astrocytes resemble their rodent counterpart but are larger in diameter. Thus, human cortical astrocytes are both larger, and structurally both more complex and more diverse, than those of rodents. On this basis, we posit that this astrocytic complexity has permitted the increased functional competence of the adult human brain.
Astrocytes provide metabolic substrates to neurons in an activity-dependent manner. However, the molecular mechanisms involved in this function, as well as its role in synaptic transmission, remain unclear. Here, we show that the gap-junction subunit proteins connexin 43 and 30 allow intercellular trafficking of glucose and its metabolites through astroglial networks. This trafficking is regulated by glutamatergic synaptic activity mediated by AMPA receptors. In the absence of extracellular glucose, the delivery of glucose or lactate to astrocytes sustains glutamatergic synaptic transmission and epileptiform activity only when they are connected by gap junctions. These results indicate that astroglial gap junctions provide an activity-dependent intercellular pathway for the delivery of energetic metabolites from blood vessels to distal neurons.
Sensory organs are composed of neurons, which convert environmental stimuli to electrical signals, and glia-like cells, whose functions are not well understood. To decipher glial roles in sensory organs, we ablated the sheath glial cell of the major sensory organ of Caenorhabditis elegans. We found that glia-ablated animals exhibit profound sensory deficits and that glia provide activities that affect neuronal morphology, behavior generation, and neuronal uptake of lipophilic dyes. To understand the molecular bases of these activities, we identified 298 genes whose messenger RNAs are glia-enriched. One gene, fig-1, encodes a labile protein with conserved thrombospondin TSP1 domains. FIG-1 protein functions extracellularly, is essential for neuronal dye uptake, and also affects behavior. Our results suggest that glia are required for multiple aspects of sensory organ function.
Glutamate-mediated damage to oligodendrocytes contributes to mental or physical impairment in periventricular leukomalacia (pre- or perinatal white matter injury leading to cerebral palsy), spinal cord injury, multiple sclerosis and stroke(1-4). Unlike neurons(5), white matter oligodendrocytes reportedly lack NMDA (N-methyl-D- aspartate) receptors(6,7). It is believed that glutamate damages oligodendrocytes, especially their precursor cells, by acting on calcium-permeable AMPA (alpha-amino-3-hydroxy-5-methyl- 4-isoxazole propionic acid)/kainate receptors alone(1-4) or by reversing cystine - glutamate exchange and depriving cells of antioxidant protection(8). Here we show that precursor, immature and mature oligodendrocytes in the white matter of the cerebellum and corpus callosum exhibit NMDA-evoked currents, mediated by receptors that are blocked only weakly by Mg2+ and that may contain NR1, NR2C and NR3 NMDA receptor subunits. NMDA receptors are present in the myelinating processes of oligodendrocytes, where the small intracellular space could lead to a large rise in intracellular ion concentration in response to NMDA receptor activation. Simulating ischaemia led to development of an inward current in oligodendrocytes, which was partly mediated by NMDA receptors. These results point to NMDA receptors of unusual subunit composition as a potential therapeutic target for preventing white matter damage in a variety of diseases.
ATP has been shown to be an important extracellular signaling molecule. There are two subgroups of receptors for ATP (and other purines and pyrimidines): the ionotropic P2X and the G-protein-coupled P2Y receptors. Different subtypes of these receptors have been identified by molecular biology, but little is known about their functional properties in the nervous system. Here we present data for the existence of P2 receptors in Muller (glial) cells of the human retina. The cells were studied by immunocytochemistry, electrophysiology, Ca2+-microfluorimetry, and molecular biology. They displayed both P2Y and P2X receptors. Freshly enzymatically isolated cells were used throughout the study. Although the [Ca2+](i) response to ATP was dominated by release from intracellular stores, there is multiple evidence that the ATP-induced membrane currents were caused by an activation of P2X(7) receptors. Immunocytochemistry and single-cell RT-PCR revealed the expression of P2X7 receptors by Muller cells. In patch-clamp studies, we found that (1) benzoyl-benzoyl ATP (BzATP) was the most effective agonist to evoke large inward currents and (2) the currents were abolished by P2X antagonists; however, (3) long-lasting application of BzATP did not cause an opening of large pores in addition to the cationic channels. By microfluorimetry it was shown that the P2X receptors mediated a Ca2+ influx that contributed a small component to the total [Ca2+](i) response. Activation of P2X receptors may modulate the uptake of neurotransmitters from the extracellular space by Muller cells in the retina.
Following more than 30. years of detailed investigation, it is now widely accepted that inexcitable glial cells express many of the same ion channels originally described in neurons. Some of these channels support ion homeostasis in the brain, thereby indirectly contributing to electrical signaling, while other ion channels are necessary for cell proliferation and regulation of cell volume when exposed to osmotic challenges. This article summarizes current knowledge regarding ion channel expression and function in macroglial cells.
The action of neurotransmitters can be terminated by cleavage, diffusion, binding, or cellular uptake. In some cases, uptake is accomplished by glial cells localized at or near the synapse. Glial cells express a variety of neurotransmitter uptake systems, and these systems play a fundamental role in both normal brain function and disease states. All types of glial cells-astrocytes, oligodendrocytes, and microglia-can express transporters for neurotransmitter uptake. This chapter focuses on astrocyte glutamate uptake, which is the most fully characterized of the astrocyte neurotransmitter uptake systems.
Auto-regeneration-the process of discontinuous generation of the axons from the Schwann cells of the peripheral stump without the collaboration of the trophic centers or neurons of origin-appeared at a time when there were no adequate methods for impregnating axons during the course of their continuous growth through the scar and distal segment of the sectioned nerve. Every sectioned nerve regenerates its axons by means of sprouts from the central stump which cross the scar and assail the peripheral stump to reach the external sensory and muscular terminations. Regeneration does not take place in the nervous centers. Instead of regenerative apathy, the central axons show numerous degenerating transformations. The unity of the pathological reaction in neurons demands a clarifying restriction. That the elements which have lost their principal connections persist for a greater or lesser time constitutes a strong indication of the anatomical discontinuity of nerve cells.
1) High concentration of sodium glutamate (as well as sodium aspartate) which is applied into grey matters of motor cortex in dogs, monkeys and men, generates clonic convulsions with very short latent periods.2) Small dose of sodium glutamate which is introduced into circulation in dogs improves the differentiation of conditioned salivary reflexes during 20 minutes after its administration, and continues its action for some hours.3) The above two aspects of the effect of sodium glutamate must be attributable to the direct physiological action of the chemicals on the central nervoos system in higher animals.
The focus of the current research projects in my laboratory revolves around the question of metabolic plasticity of neuron-glia coupling. Our hypothesis is that behavioural conditions, such as for example learning or the sleep-wake cycle, in which synaptic plasticity is well documented, or during specific pathological conditions, are accompanied by changes in the regulation of energy metabolism of astrocytes. We have indeed observed that the 'metabolic profile' of astrocytes is modified during the sleep-wake cycle and during conditions mimicking neuroinflammation in the presence or absence of amyloid-β. The effect of amyloid-β on energy metabolism is dependent on its state of aggregation and on internalization of the peptide by astrocytes. Distinct patterns of metabolic activity could be observed during the learning and recall phases in a spatial learning task. Gene expression analysis in activated areas, notably hippocampous and retrosplenial cortex, demonstrated that the expression levels of several genes implicated in astrocyte-neuron metabolic coupling are enhanced by learning. Regarding metabolic plasticity during the sleep-wake cycle, we have observed that the level of expression of a panel of selected genes, which we know are key for neuron-glia metabolic coupling, is modulated by sleep deprivation.
This article concludes a series of papers concerned with the flow of electric current through the surface membrane of a giant nerve fibre (Hodgkinet al., 1952,J. Physiol.116, 424–448; Hodgkin and Huxley, 1952,J. Physiol.116, 449–566). Its general object is to discuss the results of the preceding papers (Section 1), to put them into mathematical form (Section 2) and to show that they will account for conduction and excitation in quantitative terms (Sections 3–6).
Developmental function – producing new neural cellsDevelopmental function – neuronal guidanceRegulation of synaptogenesis and control of synaptic maintenance and eliminationStructural function – creation of the functional microarchitecture of the brainVascular function – creation of glial–vascular interface (blood–brain barrier) and glia–neurone–vascular unitsRegulation of brain microcirculationIon homeostasis in the extracellular spaceRegulation of extracellular glutamate concentrationWater homeostasis and regulation of the extracellular space volumeNeuronal metabolic supportAstroglia regulate synaptic transmissionIntegration in neuronal–glial networksAstrocytes as cellular substrate of memory and consciousness?
This study was aimed at characterizing ATP‐induced rises in cytosolic free calcium ion, [Ca ²⁺ ] i , in a population of rat striatal astrocytes loaded with the fluorescent Ca ²⁺ probe Fura2, by means of fluorescence spectrometry.
ATP triggered a fast and transient elevation of [Ca ²⁺ ] i in a concentration‐dependent manner. The responses of the purine analogues 2‐methylthio‐ATP (2‐meSATP), adenosine‐5′‐O‐(2‐thiodiphosphate) (ADPβS), as well as uridine‐5′‐triphosphate (UTP) resembled that of ATP, while α,β‐methylene‐ATP (α,β‐meATP) and β,γ‐methylene‐ATP (β,γ‐meATP) were totally ineffective.
Suramin (50 μ M ) had only a minor effect on the ATP response, whereas pyridoxal phosphate‐6‐azophenyl‐2′,4′‐disulphonic acid (PPADS) (5 μ M ) significantly depressed the maximum response.
Extracellular Ca ²⁺ did not contribute to the observed [Ca ²⁺ ] i rise: removing calcium from the extracellular medium (with 1 m M EGTA) or blocking its influx by means of either Ni ²⁺ (1 m M ) or Mn ²⁺ (1 m M ) did not modify the nucleotide responses.
Furthermore, after preincubation with 10 μ M thapsigargin, the nucleotide‐evoked [Ca ²⁺ ] i increments were completely abolished. In contrast, 10 m M caffeine did not affect the responses, suggesting that thapsigargin‐, but not caffeine/ryanodine‐sensitive stores are involved.
Both application of the G‐protein blocker guanosine‐5′‐O‐(2‐thiodiphosphate) (GDPβS) (1 m M ) and preincubation with pertussis toxin (PTx) (350 ng ml ⁻¹ ) partially inhibited the nucleotide‐mediated responses. Moreover, the phospholipase C (PLC) inhibitor U‐73122, but not its inactive stereoisomer U‐73343 (5 μ M ), significantly reduced the ATP‐evoked [Ca ²⁺ ] i rise.
In conclusion, our results suggest that, in rat striatal astrocytes, ATP‐elicited elevation of [Ca ²⁺ ] i is due solely to release from intracellular stores and is mediated by a G‐protein‐linked P2Y receptor, partially sensitive to PTx and coupled to PLC.
British Journal of Pharmacology (1997) 121 , 1700–1706; doi: 10.1038/sj.bjp.0701293
Neurotransmitters released at synapses mediate Ca2+ signaling in astrocytes in CNS grey matter. Here, we show that ATP and glutamate evoke these Ca2+ signals in white matter astrocytes of the mouse optic nerve, a tract that contains neither neuronal cell bodies nor synapses. We further demonstrate that action potentials along white matter axons trigger the release of ATP and the intercellular propagation of astroglial Ca2+ signals. These mechanisms were studied in astrocytes in intact optic nerves isolated from transgenic mice expressing enhanced green fluorescent protein (EGFP) under control of the human glial fibrillary acidic protein promoter (GFAP) by Fura-2 ratiometric Ca2+ imaging. ATP evoked astroglial Ca2+ signals predominantly via metabotropic P2Y1 and ionotropic P2X7 purinoceptors. Glutamate acted on both AMPA- and NMDA-type receptors, as well as on group I mGlu receptors to induce an increase in astroglial [Ca2+]i. The direct Ca2+ signal evoked by glutamate was small, and the main action of glutamate was to trigger the release of the “gliotransmitter” ATP by a mechanism involving P2X7 receptors; propagation of the glutamate-mediated Ca2+ signal was significantly reduced in P2X7 knock-out mice. Furthermore, axonal action potentials and mechanical stimulation of astrocytes both induced the release of ATP, to propagate Ca2+ signals in astrocytes and neighboring EGFP-negative glia. Our data provide a model of multiphase axon–glial signaling in the optic nerve as follows: action potentials trigger axonal release of ATP, which evokes further release of ATP from astrocytes, and this acts by amplifying the initiating signal and by transmitting an intercellular Ca2+ wave to neighboring glia. © 2008 Wiley-Liss, Inc.
Two main characteristics of astrocytes are their elaborated intracellular calcium signaling and their high degree of intercellular communication mediated by gap junctional channels. In these cells a number of studies have contributed to demonstrate that the combination of these two properties provides a basis for a long-range signaling system within the brain. Intercellular calcium signaling, also termed calcium waves, allows astrocytes to communicate with each other and to interact with adjacent neurons. Most of the intra- and inter-cellular events involved in the initiation and propagation phases of this process has now been identified. This sequence of events includes the permeability of gap junction channels, which at the time-scale for calcium waves propagation, are likely permeated rather than closed by Ca2+ and/or related signaling molecules like IP3. In addition, in some studies an external component have been reported to participate to the propagation process. Finally, the control of the spread of intercellular calcium signaling has been demonstrated to occur at several levels including phospholipase C, IP3 receptors, intracellular Ca2+ stores, and cytoplasmic Ca2+ buffering. Accordingly, normal and pathological situations that affect one or several of these steps can be predicted to influence on astrocytic calcium waves. GLIA 24:50–64, 1998. © 1998 Wiley-Liss, Inc.
The distribution of the P2X2 receptor subunit of the adenosine 5′-triphosphate (ATP)-gated ion channels was examined in the adult rat central nervous system (CNS) by using P2X2 receptor-specific antisera and riboprobe-based in situ hybridisation. P2X2 receptor mRNA expression matched the P2X2 receptor protein localisation. An extensive expression pattern was observed, including: olfactory bulb, cerebral cortex, hippocampus, habenula, thalamic and subthalamic nuclei, caudate putamen, posteromedial amygdalo-hippocampal and amygdalo-cortical nuclei, substantia nigra pars compacta, ventromedial and arcuate hypothalamic nuclei, supraoptic nucleus, tuberomammillary nucleus, mesencephalic trigeminal nucleus, dorsal raphe, locus coeruleus, medial parabrachial nucleus, tegmental areas, pontine nuclei, red nucleus, lateral superior olive, cochlear nuclei, spinal trigeminal nuclei, cranial motor nuclei, ventrolateral medulla, area postrema, nucleus of solitary tract, and cerebellar cortex. In the spinal cord, P2X2 receptor expression was highest in the dorsal horn, with significant neuronal labeling in the ventral horn and intermediolateral cell column. The identification of extensive P2X2 receptor immunoreactivity and mRNA distribution within the CNS demonstrated here provides a basis for the P2X receptor antagonist pharmacology reported in electrophysiological studies. These data support the role for extracellular ATP acting as a fast neurotransmitter at pre- and postsynaptic sites in processes such as sensory transmission, sensory-motor integration, motor and autonomic control, and in neuronal phenomena such as long-term potentiation (LTP) and depression (LTD). Additionally, labelling of neuroglia and fibre tracts supports a diverse role for extracellular ATP in CNS homeostasis. J. Comp. Neurol. 407:11–32, 1999. © 1999 Wiley-Liss, Inc.
Astrocyte cultures prelabelled with either [3H]-inositol or 45Ca2+ were exposed to ATP and its hydrolysis products. ATP and ADP, but not AMP and adenosine, produced increases in the accumulation of intracellular 3H-labelled inositol phosphates (IP), efflux of 45Ca2+, and release of thromboxane A2 (TXA2). Whereas ATP-stimulated 3H-IP accumulation was unaffected, its ability to promote TXA2 release was markedly reduced by mepacrine, an inhibitor of phospholipase A2 (PLA2). ATP-evoked 3H-IP production was also spared following treatment with the cyclooxygenase inhibitor, indomethacin. We conclude that ATP-induced phosphoinositide (PPI) breakdown and 45Ca2+ mobilisation occurred in parallel with, if not preceded, the release of TXA2. Following depletion of intracellular Ca2+ with a brief preexposure to ATP in the absence of extracellular Ca2+, the release of TXA2 in response to a subsequent ATP challenge was greatly reduced when compared with control. These results suggest that mobilisation of cytosolic Ca2+ may be the stimulus for PLA2 activation and, thus, TXA2 release. Stimulation of -adrenoceptors also caused PPI breakdown and 45Ca2+ efflux but not TXA2 release. The effects of ATP and noradrenaline (NA) on 3H-IP accumulation were additive, but their combined ability to increase 45Ca2+ efflux was not. Interestingly, in the presence of NA, ATP-stimulated TXA2 release was reduced. Our data provide evidence that functional P2-purinergic receptors are present on astrocytes and that ATP is the first physiologically relevant stimulus found to initiate prostanoid release from these cells.
We previously demonstrated that the inhibitory neurotransmitter glycine induced membrane currents in glial cells from rat spinal cord. In the present study, the patch-clamp technique was combined with the reverse transcription-mediated PCR to analyze the glycine receptor-subunit expression in individual glial cells of rats age 3–18 days. Using the patch-clamp technique in the whole-cell configuration, glial cells were identified by their membrane current pattern and tested for responsiveness to glycine. Subsequently, the cytoplasm was harvested followed by reverse transcription of total cytoplasmic RNA. Subunit-specific cDNA fragments were amplified and analyzed by agarose gel electrophoresis, Southern blotting, and sequencing. In all glial cell types investigated, transcripts of the α1 subunit, but not of α2 or α3 subunits, were detected. In addition, about one-half the glial cells analyzed contained β-subunit mRNA. These results illustrate that glial cells of rat spinal cord express functional glycine receptors in contrast to cultured glial cells. Glial cells are in intimate contact with synaptic regions making it likely that these nonneuronal receptors may be activated during glycinergic transmission and may trigger yet unknown responses in the glial cells.
Reactive gliosis is a prominent morphological feature of mesial temporal lobe epilepsy. Because astrocytes express glutamate receptors, we examined changes in metabotropic glutamate receptor (mGluR) 2/3, mGluR5 and transforming growth factor (TGF)-β in glial cells of the hippocampal regions in an experimental rat model of spontaneous seizures. Rats that exhibited behavioural status epilepticus (SE) directly after 1 h of electrical angular bundle stimulation, displayed chronic spontaneous seizures after a latent period of 1–2 weeks as observed using continuous electrographic monitoring. SE resulted in hypertrophy of astrocytes and microglia activation throughout the hippocampus as revealed by immunolabelling studies. A dramatic, seizure intensity-dependent increase in vimentin immunoreactivity (a marker for reactive astrocytes) was revealed in CA3 and hilar regions where prominent neuronal loss occurs. Increased vimentin labelling was first apparent 24 h after onset of SE and persisted up to 3 months. mGluR2/3 and mGluR5 protein expression increased markedly in glial cells of CA3 and hilus by 1 week after SE, and persisted up to 3 months after SE. Double immunolabelling of brain sections with vimentin confirmed co-localization with glial fibrillary acidic protein (GFAP), mGluR2/3 and mGluR5 in reactive astrocytes. TGF-β, a cytokine implicated in mGluR3-mediated neuroprotection, was also upregulated during the first 3 weeks after SE throughout the hippocampus. This study demonstrates seizure-induced upregulation of two mGluR subtypes in reactive astrocytes, which − together with the increased production of TGF-β − may represent a novel mechanism for modulation of glial function and for changes in glial-neuronal communication in the course of epileptogenesis.
This article concludes a series of papers concerned with the flow of electric current through the surface membrane of a giant
nerve fibre (Hodgkinet al., 1952,J. Physiol.
116, 424–448; Hodgkin and Huxley, 1952,J. Physiol.
116, 449–566). Its general object is to discuss the results of the preceding papers (Section 1), to put them into mathematical
form (Section 2) and to show that they will account for conduction and excitation in quantitative terms (Sections 3–6).
Morphine stimulates nitric oxide (NO) release in human endothelial cells. To determine whether this mechanism also occurs in invertebrates, the musselMytilus edulis was studied. Exposure of excised ganglia to morphine for 24 h resulted in a significant dose-dependent decrease in rnicroglial egress that was naloxone sensitive. In coincubating the excised ganglia with morphine and the nitric oxide synthase inhibitor, N omega-nitro-l-arginine methyl ester (l-NAME), an increase in microglial egress was observed, suggesting that morphine may stimulate microglia to release NO. Morphine exposure to these cells in vitro resulted in NO release (39.4 ± 4.9 nM), a phenomenon found to be naloxone sensitive (10−6 M; NO level = 5.9 ± 2.6 nM) andl-NAME sensitive (10−4 M; NO level = 2.8 ± 1.8 nM). Opioid peptides did not stimulate NO release, indicating that the process was mediated by the opiate alkaloid selectiveμ3 receptor. Coincubation of microglia withl-arginine or the superoxide scavenger, superoxide dismutase, resulted in significantly higher NO levels observed following morphine stimulation. Taken together, the data demonstrate that morphine can stimulate NO release in cells obtained from an invertebrate that represents an animal 500 million years divergent in evolution from man, underscoring the significance of this process and further substantiating the critical importance of morphine as a naturally occurring signal molecule.
Recent work shows that glial cells in species throughout the animal kingdom appear to contribute to the functioning of the neurones and are equipped to receive signals from them. However, the detailed mechanisms of the signalling and its role in vivo are generally unclear. Parts of some invertebrate nervous systems are particularly favourable for addressing these problems, and the four preparations that have been studied most intensively are the subject of this review. Between the giant axons and their Schwann glial cells in squid and crayfish, within snail brain, and in leech ganglion, there appear to be multiple, and in some cases very complex, signalling pathways, whose precise functions remain to be elucidated. In bee retina only a single signal to the glia has been demonstrated, and its function appears to be to activate transfer of metabolic substrates to the photoreceptor neurones.Trends Neurosci. (1996) 19, 358–362
The Ca2+ store and sink in the endoplasmic reticulum (ER) is important for Ca2+ signal integration and for conveyance of information in spatial and temporal domains. Textbooks regard the ER as one continuous network, but biochemical and biophysical studies revealed apparently discrete ER Ca2+ stores. Recent direct studies of ER lumenal Ca2+ movements show that this organelle system is one continuous Ca2+ store, which can function as a Ca2+ tunnel. The concept of a fully connected ER network is entirely compatible with evidence indicating that the distribution of Ca2+-release channels in the ER membrane is discontinuous with clustering in certain localities.
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For decades, astrocytes have been regarded as passive partners of neurons in central nervous system (CNS) function. Studies of the last 20 years, however, challenged this view by demonstrating that astrocytes possess functional receptors for neurotransmitters and respond to their stimulation via release of gliotransmitters, including glutamate. Notably, astrocytes react to synaptically released neurotransmitters with intracellular calcium ([Ca(2+)]) elevations, which result in the release of glutamate via regulated exocytosis and, possibly, other mechanisms. These findings have led to a new concept of neuron-glia intercommunication where astrocytes play an unsuspected dynamic role by integrating neuronal inputs and modulating synaptic activity. The additional observation that glutamate release from astrocytes is controlled by molecules linked to inflammatory reactions, such as the cytokine tumor necrosis factor alpha (TNFalpha) and prostaglandins (PGs), suggests that glia-to-neuron signalling may be sensitive to changes in the production of these mediators occurring in pathological conditions. Indeed, a local, parenchymal brain inflammatory reaction (neuroinflammation) characterized by astrocytic and microglial activation has been reported in several neurodegenerative disorders, including AIDS dementia complex, Alzheimer's disease and amyotrophic lateral sclerosis. This transition may be accompanied by functional de-regulation and even degeneration of the astrocytes with the consequent disruption of the cross-talk normally occurring between these cells and neurons. Incorrect neuron-astrocyte interactions may be involved in neuronal derangement and contribute to disease development. The findings reported in this review suggest that a better comprehension of the glutamatergic interplay between neurons and astrocytes may provide information about normal brain function and also highlight potential molecular targets for therapeutic interventions in pathology.
The coupling between synaptic activity and glucose utilization (neurometabolic coupling) is a central physiologic principle of brain function that has provided the basis for 2-deoxyglucose-based functional imaging with positron emission tomography. Approximately 10 y ago we provided experimental evidence that indicated a central role of glutamate signaling on astrocytes in neurometabolic coupling. The basic mechanism in neurometabolic coupling is the glutamate-stimulated aerobic glycolysis in astrocytes, such that the sodium-coupled reuptake of glutamate by astrocytes and the ensuing activation of the Na(+)-K(+) ATPase triggers glucose uptake and its glycolytic processing, which results in the release of lactate from astrocytes. Lactate can then contribute to the activity-dependent fueling of the neuronal energy demands associated with synaptic transmission. Analyses of this coupling have been extended in vivo and have defined the methods of coupling for inhibitory neurotransmission as well as its spatial extent in relation to the propagation of metabolic signals within the astrocytic syncytium. On the basis of a large body of experimental evidence, we proposed an operational model, "the astrocyte-neuron lactate shuttle." A series of results obtained by independent laboratories have provided further support for this model. This body of evidence provides a molecular and cellular basis for interpreting data that are obtained with functional brain imaging studies.
There is increasing evidence that glial cells, in particular astrocytes, interact dynamically with neurons. The well-known anatomofunctional organization of neurons in the barrel cortex offers a suitable and promising model to study such neuroglial interaction. This review summarizes and discusses recent in vitro as well as in vivo works demonstrating that astrocytes receive, integrate, and respond to neuronal signals. In addition, they are active elements of brain metabolism and exhibit a certain degree of plasticity that affects neuronal activity. Altogether these findings indicate that the barrel cortex presents glial compartments overlapping and interacting with neuronal compartments and that these properties help define barrels as functional and independent units. Finally, this review outlines how the use of the barrel cortex as a model might in the future help to address important questions related to dynamic neuroglia interaction.
Astrocytes were classically considered as simple supportive cells for neurons without a significant role in information processing by the nervous system. However, considerable amounts of evidence obtained by several groups during the past years demonstrated the existence of a bidirectional communication between astrocytes and neurons, which prompted a re-examination of the role of astrocytes in the physiology of the nervous system. While neurons base their excitability on electrical signals generated across the membrane, astrocytes base their cellular excitability on variations of the Ca2+ concentration in the cytosol. This article discusses our current knowledge of the properties of the synaptically evoked astrocyte Ca2+ signal, which reveals that astrocytes display integrative properties for synaptic information processing. Astrocytes respond selectively to different axon pathways, discriminate between the activity of different synapses and their Ca2+ signal is non-linearly modulated by the simultaneous activity of different synaptic inputs. Furthermore, this Ca2+ signal modulation depends on astrocyte cellular intrinsic properties and is bidirectionally regulated by the level of synaptic activity. Finally, astrocyte Ca2+ elevations can trigger the release of gliotransmitters, which modulate neuronal activity as well as synaptic transmission and plasticity, hence granting the bidirectional communication with neurons. Consequently, astrocytes can be considered as cellular elements involved in information processing by the nervous system.
Purines appear to be the most primitive and widespread chemical messengers in the animal and plant kingdoms. The evidence for purinergic signalling in plants, invertebrates and lower vertebrates is reviewed. Much is based on pharmacological studies, but important recent studies have utilized the techniques of molecular biology and receptors have been cloned and characterized in primitive invertebrates, including the social amoeba Dictyostelium and the platyhelminth Schistosoma, as well as the green algae Ostreococcus, which resemble P2X receptors identified in mammals. This suggests that contrary to earlier speculations, P2X ion channel receptors appeared early in evolution, while G protein-coupled P1 and P2Y receptors were introduced either at the same time or perhaps even later. The absence of gene coding for P2X receptors in some animal groups [e.g. in some insects, roundworms (Caenorhabditis elegans) and the plant Arabidopsis] in contrast to the potent pharmacological actions of nucleotides in the same species, suggests that novel receptors are still to be discovered.
Astrocytes modulate neuronal activity by releasing chemical transmitters via a process termed gliotransmission. The role of this process in the control of behavior is unknown. Since one outcome of SNARE-dependent gliotransmission is the regulation of extracellular adenosine and because adenosine promotes sleep, we genetically inhibited the release of gliotransmitters and asked if astrocytes play an unsuspected role in sleep regulation. Inhibiting gliotransmission attenuated the accumulation of sleep pressure, assessed by measuring the slow wave activity of the EEG during NREM sleep, and prevented cognitive deficits associated with sleep loss. Since the sleep-suppressing effects of the A1 receptor antagonist CPT were prevented following inhibition of gliotransmission and because intracerebroventricular delivery of CPT to wild-type mice mimicked the transgenic phenotype, we conclude that astrocytes modulate the accumulation of sleep pressure and its cognitive consequences through a pathway involving A1 receptors.
NG2 cells (also known as polydendrocytes) are a population of CNS cells that are distinct from neurons, mature oligodendrocytes, astrocytes and microglia. They can be identified by the expression of the proteoglycan NG2, have a highly branched morphology and are distributed throughout the grey and white matter. They differentiate into oligodendrocytes in vitro and have often been equated with oligodendrocyte precursor cells. However, whether polydendrocytes are multipotential cells that can give rise to neurons and astrocytes as well as oligodendrocytes is now highly debated. Furthermore, electrophysiological studies indicate that polydendrocytes receive synaptic input from neurons, suggesting that they are integrated in the neural network. This Review highlights recent findings and unresolved questions related to the lineage and function of polydendrocytes in the CNS.
Purinergic receptors, represented by several families, are arguably the most abundant receptors in living organisms and appeared early in evolution. After slow acceptance, purinergic signalling in both peripheral and central nervous systems is a rapidly expanding field. Here, we emphasize purinergic co-transmission, mechanisms of release and breakdown of ATP, ion channel and G-protein-coupled-receptor subtypes for purines and pyrimidines, the role of purines and pyrimidines in neuron-glial communication and interactions of this system with other transmitter systems. We also highlight recent data involving purinergic signalling in pathological conditions, including pain, trauma, ischaemia, epilepsy, migraine, psychiatric disorders and drug addiction, which we expect will lead to the development of therapeutic strategies for these disorders with novel mechanisms of action.
The neuronal doctrine, which shaped the development of neuroscience, was born from a long-lasting struggle between reticularists, who assumed internal continuity of neural networks and neuronists, who defined the brain as a network of physically separated cellular entities, defined as neurones. Modern views regard the brain as a complex of constantly interacting cellular circuits, represented by neuronal networks embedded into internally connected astroglial syncytium. The neuronal-glial circuits endowed with distinct signalling cascades form a 'diffuse nervous net' suggested by Golgi, where millions of synapses belonging to very different neurones are integrated first into neuronal-glial-vascular units and then into more complex structures connected through glial syncytium. These many levels of integration, both morphological and functional, presented by neuronal-glial circuitry ensure the spatial and temporal multiplication of brain cognitive power.