No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
The Nature of Early Astroglial Protection − Fast Activation and Signaling
... Traumatic brain injury (TBI) refers to a sudden trauma caused by traffic accidents, wars, violence, terrorism, falls, and sporting activity [1]. TBI is currently the primary cause of human death in young adults and one of the leading causes of fatality and disability across all ages worldwide, resulting in annual global economic losses of amounting to $US400 billion [2][3][4]. ...
... In addition, astrocytes provide functional support for neurons, including the recycling of the neurotransmitter glutamate, the most potent neurotoxin in the brain, via glutamate transporters (Fig. 2), the glutamate-glutamine shuttle system, and cystine-glutamate antiporter system [47][48][49]. Astrocytes play a role in the release of neurotrophic factors and gliotransmitters such as glutamate, ATP, γ-aminobutyrate (GABA), and D-serine [1,15,50]; the synthesis of glutamine, cholesterol, superoxide dismutases, glutathione, ascorbate and thrombospondin (TSP)-1 and 2 [9,51,52]. Astrocytes are also involved in the regulation of energy metabolism by the conversion of glucose into lactate [53][54][55] and the regulation of neuronal activation and water homeostasis through extracellular ion concentrations [56][57][58][59]. ...
... Astrocytes play a crucial role in regulating excitatory chemical transmission via glutamate transporters (Fig. 2), glutamate-glutamine shuttle system, and cystine-glutamate antiporter system. However, the impairment of astrocytic glutamate uptake and GABA release lead to glutamate excitotoxicity as well as ion and water imbalance post-TBI [1,9]. Glutamate is the primary excitatory neurotransmitter and the most potent neurotoxin once concentrated in the extracellular space of CNS. ...
Traumatic brain injury (TBI) is one of the leading causes of fatality and disability worldwide. Despite its high prevalence, effective treatment strategies for TBI are limited. Traumatic brain injury induces structural and functional alterations of astrocytes, the most abundant cell type in the brain. As a way of coping with the trauma, astrocytes respond in diverse mechanisms that result in reactive astrogliosis. Astrocytes are involved in the physiopathologic mechanisms of TBI in an extensive and sophisticated manner. Notably, astrocytes have dual roles in TBI, and some astrocyte-derived factors have double and opposite properties. Thus, the suppression or promotion of reactive astrogliosis does not have a substantial curative effect. In contrast, selective stimulation of the beneficial astrocyte-derived molecules and simultaneous attenuation of the deleterious factors based on the spatiotemporal-environment can provide a promising astrocyte-targeting therapeutic strategy. In the current review, we describe for the first time the specific dual roles of astrocytes in neuronal plasticity and reconstruction, including neurogenesis, synaptogenesis, angiogenesis, repair of the blood-brain barrier, and glial scar formation after TBI. We have also classified astrocyte-derived factors depending on their neuroprotective and neurotoxic roles to design more appropriate targeted therapies. Video Abstract.
... Intracellular high-[K + ] i and low-[Na + ] i holds for excitable tissues such as nerve and muscle [1]. Further than nerves, Na + transients may activate astrocytes and neuro-glia coupling via uptake of glutamate (Glu) [2][3][4][5][6][7]. Here we discuss the details of the active astrocytic transport of major excitatory neurotransmitter in the brain, Glu. ...
... The Glu-uptake induced activation of Na + dynamics in astrocytes discussed in this paper represents only local players of an extensive network of the tripartite synapse, the focal point in neuro-glia coupling [2][3][4][5][6][7]. We and others increasingly recognized the role of potential interplay of Glu-uptake and other Na + -dependent transport processes as contributing factors in various diseases, such as Huntington, Alzheimer, Tourette, epilepsy, stroke, demyelinating diseases, hyperammonemia, cardiac ischemia and cancer [2,14,[38][39][40][41][42][43][44][45][46][47][48][49][50][51][52]. ...
... The Glu-uptake induced activation of Na + dynamics in astrocytes discussed in this paper represents only local players of an extensive network of the tripartite synapse, the focal point in neuro-glia coupling [2][3][4][5][6][7]. We and others increasingly recognized the role of potential interplay of Glu-uptake and other Na + -dependent transport processes as contributing factors in various diseases, such as Huntington, Alzheimer, Tourette, epilepsy, stroke, demyelinating diseases, hyperammonemia, cardiac ischemia and cancer [2,14,[38][39][40][41][42][43][44][45][46][47][48][49][50][51][52]. ...
The synergy between synaptic Glu release and astrocytic Glu-Na+ symport is essential to the signalling function of the tripartite synapse. Here we used kinetic data of astrocytic Glu transporters (EAAT) and the Na+/Ca2+ exchanger (NCX) to simulate Glu release, Glu uptake and subsequent Na+ and Ca2+ dynamics in the astrocytic leaflet microdomain following single release event. Model simulations show that Glu-Na+ symport differently affect intracellular [Na+] in synapses with different extent of astrocytic coverage. Surprisingly, NCX activity alone has been shown to generate markedly stable, spontaneous Ca2+ oscillation in the astrocytic leaflet. These on-going oscillations appear when NCX operates either in the forward or reverse direction. We conjecture that intrinsic NCX activity may play a prominent role in the generation of astrocytic Ca2+ oscillations.
... Maintenance of the significant energy demand of balanced Glu-GABA signaling depends on proper neuroglia metabolic coupling in various physiological and disease conditions [14,68,69,89,129,131,149,174,200,213,231]; for reviews see [4,70,86,87,96,97,110,184,216]. This dependency is highlighted by the observation that complexes between the astrocytic Glu transporter EAAT2 and the α2 isoform of Na + /K + -ATPase are concentrated in the perisynaptic astrocytic processes (PAPs), which also indicates a unique role for Glu homeostasis [123]. ...
... Also, extrasynaptic δ-containing GABA A receptors in the NAc dorsomedial shell played a role in alcohol intake [138]. It is proposed therefore that the astrocytic Glu-GABA exchange mechanism revealed in the hippocampal formation and the striatum [68, 69, 231]; for reviews see [86,87,93,96,97,216] may also modulate NAc functions by adapting tonic inhibition. It is tempting to speculate about the likely correlation of connexin 43 (Cx43)-positive astrocytes in the NAc [129] with the expression of astrocytic GAT3 and EAAT2 in light of the Glu-GABA exchange mechanisms. ...
... It is tempting to speculate about the likely correlation of connexin 43 (Cx43)-positive astrocytes in the NAc [129] with the expression of astrocytic GAT3 and EAAT2 in light of the Glu-GABA exchange mechanisms. Also, the induction of EAAT2 expression and trafficking or the motility of the PAPs ( [87] and references cited therein) raises the possibility of excitationinduced co-localization of EAAT2 with GAT3 [71, 110,135,144,152]. It is noteworthy that the Bgliocentric( references cited above, and [172]) and Bneurocentric[ 147] views of inhibitory plasticity corroborate in terms of the chloride gradient shift across the neuronal membrane. ...
Part of the ventral striatal division, the nucleus accumbens (NAc) drives the circuit activity of an entire macrosystem about reward like a “flagship,” signaling and leading diverse conducts. Accordingly, NAc neurons feature complex inhibitory phenotypes that assemble to process circuit inputs and generate outputs by exploiting specific arrays of opposite and/or parallel neurotransmitters, neuromodulatory peptides. The resulting complex combinations enable versatile yet specific forms of accumbal circuit plasticity, including maladaptive behaviors. Although reward signaling and behavior are elaborately linked to neuronal circuit activities, it is plausible to propose whether these neuronal ensembles and synaptic islands can be directly controlled by astrocytes, a powerful modulator of neuronal activity. Pioneering studies showed that astrocytes in the NAc sense citrate cycle metabolites and/or ATP and may induce recurrent activation. We argue that the astrocytic calcium, GABA, and Glu signaling and altered sodium and chloride dynamics fundamentally shape metaplasticity by providing active regulatory roles in the synapse- and network-level flexibility of the NAc.
... An increasing body of evidence demonstrates the existence of neuronal activity-dependent or even independent activation of astrocytes showing Ca 2+ transients [Hirase et al., 2004;Nimmerjahn et al., 2009;Poskanzer and Yuste, 2016;Savtchenko and Rusakov R.A., 2014;Szabó et al., 2017;Wang et al., 2006; for reviews see Bazargani and Attwell, 2016;Kardos et al., 2017;Rusakov, 2015;Verkhratsky and Nedergaard, 2018; and references cited therein]. Importantly, these astrocytes have the potential to significantly modulate synaptic transmission (Barres, 2008;Gourine and Kasparov, 2011). ...
... Here, we argue for a multifaceted role of astrocytic Glu transporters in brain homeostasis, neuroprotection and excitotoxicity [Canul-Tec et al., 2017;Kardos et al., 2017;Verkhratsky and Nedergaard, 2018]. In spite of the immense variety of diverse functions, a closer inspection of astrocytic EAAT2 pinpoints similarities of structural prerequisites for selective cation transport in channels, pumps and transporters [Gouaux and Mackinnon, 2005;Silverstein et al., 2018], suggesting major roles for dynamic localization and coupling to functional proteins. ...
... In addition to boosting Glu→Gln metabolism [Boulland et al., 2003;Martínez-Lozada and Ortega, 2015;Schousboe, 2019;Zhou and Danbolt, 2014], and critically hyperammonemia ([Cabrera-Pastor et al., 2018;Fried et al., 2017;Kardos et al., 2017 and references cited therein), Glu:Na + symport through EAAT2 may also stimulate Gln release through the non-electrogenic neurotransmitter sodium symporter SNAT3 [Todd et al., 2017]. Moreover, oxidative metabolism in both astrocytes and neurons determines the rate of Glu-Gln cycle [Sonnay et al., 2017;Uwechue et al., 2012]. ...
Glutamatergic transmission composed of the arriving of action potential at the axon terminal, fast vesicular Glu release, postsynaptic Glu receptor activation, astrocytic Glu clearance and Glu→Gln shuttle is an abundantly investigated phenomenon. Despite its essential role, however, much less is known about the consequences of the mechanistic connotations of Glu:Na+ symport. Due to the coupled Na+ transport, Glu uptake results in significantly elevated intracellular astrocytic [Na+] that markedly alters the driving force of other Na+-coupled astrocytic transporters. The resulting GABA and Gln release by reverse transport through the respective GAT-3 and SNAT3 transporters help to re-establish the physiological Na+ homeostasis without ATP dissipation and consequently leads to enhanced tonic inhibition and replenishment of axonal glutamate pool. Here, we place this emerging astrocytic adjustment of synaptic excitability into the centre of future perspectives.
... This copper electron transfer-coupled structural alteration of coordination at copper sites in proteins [105,106] can be envisaged as a molecular machine [107][108][109] switched on and driven by the redox disproportionation of copper. These molecular motions permit straight energy transfer from O 2 to intrinsic cellular processes, potentially supporting fast neuronal signalling and remodelling of neuro-glia coupling [110] within the brain. ...
... Several lines of evidence demonstrate memory deficits concurrent with copper deposition in the choroid plexus, astrocyte swelling (Alzheimer type II cells), astrogliosis and neuronal degeneration in the cerebral cortex, and augmented levels of copper and zinc in the hippocampus of chronically copper-intoxicated rats [337]. Furthermore, these and the other findings concerning the role for astrocytes in brain activity, dis-homeostasis and asscociated diseases [110,[338][339][340][341] and brain copper and pA homeostasis in particular [179,180,342,343] may provide support for new astrocyte-centric directions for therapeutic intervention. It can also be depicted by the "gliocentric" alternative of the "neurocentric" STP workflow suggested by Chang [336] possibly associated with major astroglial processes and players of Glu and ammonia homeostasis underlying excitation-inhibition balance in brain [110]. ...
... Furthermore, these and the other findings concerning the role for astrocytes in brain activity, dis-homeostasis and asscociated diseases [110,[338][339][340][341] and brain copper and pA homeostasis in particular [179,180,342,343] may provide support for new astrocyte-centric directions for therapeutic intervention. It can also be depicted by the "gliocentric" alternative of the "neurocentric" STP workflow suggested by Chang [336] possibly associated with major astroglial processes and players of Glu and ammonia homeostasis underlying excitation-inhibition balance in brain [110]. Prevalent traumatic and ischaemic brain injuries are explored to validate the potential of the "gliocentric" concept of early therapeutic intervention. ...
Abstract Copper-containing enzymes perform fundamental functions by activating dioxygen (O2) and therefore allowing chemical energy-transfer for aerobic metabolism. The copper-dependence of O2 transport, metabolism and production of signalling molecules are supported by molecular systems that regulate and preserve tightly-bound static and weakly-bound dynamic cellular copper pools. Disruption of the reducing intracellular environment, characterized by glutathione shortage and ambient Cu(II) abundance drives oxidative stress and interferes with the bidirectional, copper-dependent communication between neurons and astrocytes, eventually leading to various brain disease forms. A deeper understanding of of the regulatory effects of copper on neuro-glia coupling via polyamine metabolism may reveal novel copper signalling functions and new directions for therapeutic intervention in brain disorders associated with aberrant copper metabolism.
... [9][10][11][12][13] TBI refers to sudden damage caused by mechanical force, occurring in traffic accidents, blast, wars, violence, terrorism, falls and sporting activity. 14 TBI is currently the major source of fatality in young adults, with an annual global economic loss of approximately US$ 400 billion. 1,2,[14][15][16] Hypoxic-ischaemic brain injury is another frequent, fatal and crippling neurologic disease, particularly perinatal hypoxia-ischaemia remains the dominating cause of acute brain injury in the neonate. ...
... 14 TBI is currently the major source of fatality in young adults, with an annual global economic loss of approximately US$ 400 billion. 1,2,[14][15][16] Hypoxic-ischaemic brain injury is another frequent, fatal and crippling neurologic disease, particularly perinatal hypoxia-ischaemia remains the dominating cause of acute brain injury in the neonate. [17][18][19] These acute brain injuries impose a heavy socio-economic burden, whereas effective therapies are still scarce. ...
Acute brain injury is the leading cause of human death and disability worldwide, which includes intracerebral haemorrhage, subarachnoid haemorrhage, cerebral ischaemia, traumatic brain injury and hypoxia‐ischaemia brain injury. Currently, clinical treatments for neurological dysfunction of acute brain injury have not been satisfactory. Osteopontin (OPN) is a complex adhesion protein and cytokine that interacts with multiple receptors including integrins and CD44 variants, exhibiting mostly neuroprotective roles and showing therapeutic potential for acute brain injury. OPN‐induced tissue remodelling and functional repair mainly rely on its positive roles in the coordination of pro‐inflammatory and anti‐inflammatory responses, blood‐brain barrier maintenance and anti‐apoptotic actions, as well as other mechanisms such as affecting the chemotaxis and proliferation of nerve cells. The blood OPN strongly parallel the OPN induced in the brain and can be used as a novel biomarker of the susceptibility, severity and outcome of acute brain injury. In the present review, we summarized the molecular signalling mechanisms of OPN as well as its overall role in different kinds of acute brain injury.
... Thus, from one side, the Na + and Ca 2+ gradients tightly control the kinetics and directionality of NCX operation, whereas any changes in NCX activity dynamically affect Na + and Ca 2+ fluxes. This complex feedback loop involves both thermodynamic and kinetic interactions of Na + and Ca 2+ with ion transport and regulatory domains of NCX (Bers, 2002;Kardos, Héja, Jemnitz, Kovács, & Palkovits, 2017;Kirischuk, Parpura, & Verkhratsky, 2012;Oheim, Schmidt, & Hirrlinger, 2017). ...
... Dynamic coupling of NCX regulation with Na + and Ca 2+ signalling is particularly relevant in specific cells types (e.g. in astrocytes), where the reversal potential of NCX (E NCX ) is close to the resting membrane potential of the cell (E m ≈ −80 mV). As the ion-exchange turnover rates of mammalian NCXs are high (∼5000 s −1 ), even small changes in allosteric regulation of NCX (Bers, 2002;Blaustein & Lederer, 1999;Khananshvili, 2014) might instantly affect the coupled Na + and Ca 2+ signalling (Kardos et al., 2017;Oheim et al., 2017;Robinson & Jackson, 2016). Even small anomalies in allosteric regulation of NCX or coupled ion-transport systems may have devastating outcomes (Boscia et al., 2016;Wagner, Maier, & Bers, 2015). ...
New findings:
What is the topic of this review? This paper overviews the links between Ca2+ and Na+ signalling in various types of cells. What advances does it highlight? This paper highlights the general importance of ionic signalling and overviews the molecular mechanisms linking Na+ and Ca2+ dynamics. In particular, the narrative focuses on the molecular physiology of plasmalemmal and mitochondrial Na+ -Ca2+ exchangers and plasmalemmal transient receptor potential channels. Functional consequences of Ca2+ and Na+ signalling for co-ordination of neuronal activity with astroglial homeostatic pathways fundamental for synaptic transmission are discussed.
Abstract:
Transmembrane ionic gradients, which are an indispensable feature of life, are used for generation of cytosolic ionic signals that regulate a host of cellular functions. Intracellular signalling mediated by Ca2+ and Na+ is tightly linked through several molecular pathways that generate Ca2+ and Na+ fluxes and are in turn regulated by both ions. Transient receptor potential (TRP) channels bridge endoplasmic reticulum Ca2+ release with generation of Na+ and Ca2+ currents. The plasmalemmal Na+ -Ca2+ exchanger (NCX) flickers between forward and reverse mode to co-ordinate the influx and efflux of both ions with membrane polarization and cytosolic ion concentrations. The mitochondrial calcium uniporter channel (MCU) and mitochondrial Na+ -Ca2+ exchanger (NCLX) mediate Ca2+ entry into and release from this organelle and couple cytosolic Ca2+ and Na+ fluctuations with cellular energetics. Cellular Ca2+ and Na+ signalling controls numerous functional responses and, in the CNS, provides for fast regulation of astroglial homeostatic cascades that are crucial for maintenance of synaptic transmission.
... Beyond the local astroglial control over synaptic activity [8][9][10][11][12] , however, little is known about the role of astrocytic networks in modulating large-scale neuronal ensembles. Exploration of the role of large-scale astrocytic networks in information processing and cognition still lags behind its neuronal counterpart 13,14 . We conceived that fundamental properties of networking astrocytes may underlie physiological network-network interaction between astrocytes and neurons. ...
... Both neuronal and astroglial Ca 2+ transients coincided with positive half-waves of the LFP signal (Fig. 3B). Spectral analysis of the LFP signal showed that both spindle (8)(9)(10)(11)(12)(13)(14) and gamma range activities were also time-locked to the positive half-waves ( Fig. 3D-G). Since gamma range activity is known to be coupled to UP states 34 , these results confirm that the positive half-waves represent the UP states, therefore increased astrocytic activity appears in parallel with enhanced neuronal firing. ...
Slow wave activity (SWA) is a characteristic brain oscillation in sleep and quiet wakefulness. Although the cell types contributing to SWA genesis are not yet identified, the principal role of neurons in the emergence of this essential cognitive mechanism has not been questioned. To address the possibility of astrocytic involvement in SWA, we used a transgenic rat line expressing a calcium sensitive fluorescent protein in both astrocytes and interneurons and simultaneously imaged astrocytic and neuronal activity in vivo. Here we demonstrate, for the first time, that the astrocyte network display synchronized recurrent activity in vivo coupled to UP states measured by field recording and neuronal calcium imaging. Furthermore, we present evidence that extensive synchronization of the astrocytic network precedes the spatial build-up of neuronal synchronization. The earlier extensive recruitment of astrocytes in the synchronized activity is reinforced by the observation that neurons surrounded by active astrocytes are more likely to join SWA, suggesting causality. Further supporting this notion, we demonstrate that blockade of astrocytic gap junctional communication or inhibition of astrocytic Ca²⁺ transients reduces the ratio of both astrocytes and neurons involved in SWA. These in vivo findings conclusively suggest a causal role of the astrocytic syncytium in SWA generation.
... The change in intracellular Ca 2+ levels is a major area of interest in the mechanistic study of the abnormal activation of astrocytes [9]. The intracellular Ca 2+ level usually increases after CNS injury and induces cell death through a variety of pathways, such as apoptosis, pyroptosis, and the accumulation of free radicals [10,11]. ...
Spinal cord injury (SCI) is one of the most devastating traumas, and the aberrant proliferation of astrocytes usually causes neurological deficits. However, the mechanism underlying astrocyte over-proliferation after SCI is unclear. Grin2c (glutamate ionotropic receptor type 2c) plays an essential role in cell proliferation. Our bioinformatic analysis indicated that Grin2c and Ca ²⁺ transport functions were inhibited in astrocytes after SCI. Suppression of Grin2c stimulated astrocyte proliferation by inhibiting the Ca ²⁺ /calmodulin-dependent protein kinase 2b (CaMK2b) pathway in vitro . By screening different inflammatory factors, interleukin 1α (IL1α) was further found to inhibit Grin2c/Ca ²⁺ /CaMK2b and enhance astrocyte proliferation in an oxidative damage model. Blockade of IL1α using neutralizing antibody resulted in increased Grin2c expression and the inhibition of astrocyte proliferation post-SCI. Overall, this study suggests that IL1α promotes astrocyte proliferation by suppressing the Grin2c/Ca ²⁺ /CaMK2b pathway after SCI, revealing a novel pathological mechanism of astrocyte proliferation, and may provide potential targets for SCI repair.
... La capacidad de las MMP para digerir la lámina basal de los capilares aumenta el riesgo de transformación hemorrágica del tejido isquémico (Anthony et al. 1997). Durante la fase isquémica aguda, el mantenimiento de la MEC es esencial para la supervivencia neuronal (Kardos et al. 2017). Sin embargo, la degradación de la MEC y su reconstitución son críticos para la recuperación del tejido (Amantea et al. 2008). ...
Abstract
Se ha llevado a cabo una revisión bibliográfica con el equipo de trabajo “the Johns Hopkins Health System”/“The Johns Hopkins Medicine Institutional Review Boards (JHM IRBs)” acerca de la neuroinflamación en la lesión cerebral isquémica. El cual refiere claramente que el accidente cerebrovascular isquémico es la primera de las cuatro enfermedades potencialmente mortales más importantes y el trastorno más repentino en todos los continentes. La neuroinflamación es activada después de cualquier estimulo inmunológico que predisponga a lesión, tanto dentro como fuera del sistema nervioso central (SNC), que puede llevar a generar tantas respuestas enfocadas a la limitación del daño y la restauración del tejido; comprende un amplio espectro de alteraciones tisulares, incluida la activación de la microglía, la inflamación vascular con daño en la barrera hematoencefálica y la inflamación mediada por inmunidad adaptativa. La microglia es esencial por sus funciones como dar soporte mecánico a las neuronas, formar tejido cicatricial después de lesiones cerebrales, eliminar residuos después de la muerte celular. Si bien la neuroinflamación se ha considerado un mediador del daño secundario, la respuesta inmune local también tiene efectos beneficiosos sobre el tejido traumatizado. Todavía no se ha encontrado que ningún agente neuroprotector sea efectivo en ensayos clínicos en humanos. La neuroinflamación en la médula espinal es un proceso muy bien caracterizado en modelos animales de dolor neuropático, pero aún hay mucho por investigar.
... Astroglia has been postulated as a potential target for treating epileptic disorders. In particular, the control wielded by astrocytes in the balance between GABA and glutamate is critical in controlling seizures [204,205]. For instance, impaired glutamate reuptake and adenosine metabolism disruption are linked to epileptiform activity [200,206,207]. ...
Epilepsy is one of the most common neurological conditions. Yearly, five million people are diagnosed with epileptic-related disorders. The neuroprotective and therapeutic effect of
(endo)cannabinoid compounds has been extensively investigated in several models of epilepsy.
Therefore, the study of specific cell-type-dependent mechanisms underlying cannabinoid effects is
crucial to understanding epileptic disorders. It is estimated that about 100 billion neurons and a
roughly equal number of glial cells co-exist in the human brain. The glial population is in charge of
neuronal viability, and therefore, their participation in brain pathophysiology is crucial. Furthermore,
glial malfunctioning occurs in a wide range of neurological disorders. However, little is known about
the impact of the endocannabinoid system (ECS) regulation over glial cells, even less in pathological
conditions such as epilepsy. In this review, we aim to compile the existing knowledge on the role of
the ECS in different cell types, with a particular emphasis on glial cells and their impact on epilepsy.
Thus, we propose that glial cells could be a novel target for cannabinoid agents for treating the
etiology of epilepsy and managing seizure-like disorders.
... The removal by glia of neurotransmitter released by neurons is one key mechanism well-known to play an essential role in regulating the extent of neuronal excitation and inhibition (cf. Allen, 2014;Kardos et al., 2017;Malik and Willnow, 2019;Valtcheva and Venance, 2019;Belov Kirdajova et al., 2020 for review). In addition, it has long been suspected that elevations in glial intracellular calcium also lead to modulation of synaptic transfer at synapses, but the precise nature and molecular mechanism(s) of such regulation by glial cells is currently an area of contentious debate (cf. ...
Small alterations in the level of extracellular H+ can profoundly alter neuronal activity throughout the nervous system. In this study, self-referencing H+-selective microelectrodes were used to examine extracellular H+ fluxes from individual astrocytes. Activation of astrocytes cultured from mouse hippocampus and rat cortex with extracellular ATP produced a pronounced increase in extracellular H+ flux. The ATP-elicited increase in H+ flux appeared to be independent of bicarbonate transport, as ATP increased H+ flux regardless of whether the primary extracellular pH buffer was 26 mM bicarbonate or 1 mM HEPES, and persisted when atmospheric levels of CO2 were replaced by oxygen. Adenosine failed to elicit any change in extracellular H+ fluxes, and ATP-mediated increases in H+ flux were inhibited by the P2 inhibitors suramin and PPADS suggesting direct activation of ATP receptors. Extracellular ATP also induced an intracellular rise in calcium in cultured astrocytes, and ATP-induced rises in both calcium and H+ efflux were significantly attenuated when calcium re-loading into the endoplasmic reticulum was inhibited by thapsigargin. Replacement of extracellular sodium with choline did not significantly reduce the size of the ATP-induced increases in H+ flux, and the increases in H+ flux were not significantly affected by addition of EIPA, suggesting little involvement of Na+/H+ exchangers in ATP-elicited increases in H+ flux. Given the high sensitivity of voltage-sensitive calcium channels on neurons to small changes in levels of free H+, we hypothesize that the ATP-mediated extrusion of H+ from astrocytes may play a key role in regulating signaling at synapses within the nervous system.
... Under this condition, inhibition of CTR1 by added Ag + (3.6 µM AgNO 3 ) eliminated the appearance of GAT-2/3 mediated tonic inhibitory currents. Since the active moiety, astrocytic GABA that mediates tonic inhibition is synthesized from putrescine, our results highlight the contribution of Cu + /Cu 2+ ratio to oxidative putrescine → GABA catabolism in astrocytes [15,21,25,26,28,29,33,34,36,70]. ...
Astrocytes serve essential roles in human brain function and diseases. Growing evidence indicates that astrocytes are central players of the feedback modulation of excitatory Glu signalling during epileptiform activity via Glu-GABA exchange. The underlying mechanism results in the increase of tonic inhibition by reverse operation of the astroglial GABA transporter, induced by Glu-Na+ symport. GABA, released from astrocytes, is synthesized from the polyamine (PA) putrescine and this process involves copper amino oxidase. Through this pathway, putrescine can be considered as an important source of inhibitory signaling that counterbalances epileptic discharges. Putrescine, however, is also a precursor for spermine that is known to enhance gap junction channel communication and, consequently, supports long-range Ca2+ signaling and contributes to spreading of excitatory activity through the astrocytic syncytium. Recently, we presented the possibility of neuron-glia redox coupling through copper (Cu+/Cu2+) signaling and oxidative putrescine catabolism. In the current work, we explore whether the Cu+/Cu2+ homeostasis is involved in astrocytic control on neuronal excitability by regulating PA catabolism. We provide supporting experimental data underlying this hypothesis. We show that the blockade of copper transporter (CTR1) by AgNO3 (3.6 µM) prevents GABA transporter-mediated tonic inhibitory currents, indicating causal relationship between copper (Cu+/Cu2+) uptake and the catabolism of putrescine to GABA in astrocytes. In addition, we show that MnCl2 (20 μM), an inhibitor of the divalent metal transporter DMT1, also prevents the astrocytic Glu-GABA exchange. Furthermore, we observed that facilitation of copper uptake by added CuCl2 (2 µM) boosts tonic inhibitory currents. These findings corroborate the hypothesis that modulation of neuron-glia coupling by copper uptake drives putrescine → GABA transformation, which leads to subsequent Glu-GABA exchange and tonic inhibition. Findings may in turn highlight the potential role of copper signaling in fine-tuning the activity of the tripartite synapse.
... Glutamate is an excitatory neurotransmitter that plays an important role in connecting memory. Synaptic transients of excitatory glutamate and inhibitory γ-aminobutyrate (GABA) play a key role in balancing excitatory and inhibitory signaling in the central nervous system (CNS) [61]. In this study, our results showed that the glutamine content was decreased in the ischemic hemisphere, while NG-R1 obviously increased glutamate levels, especially in the striatum. ...
Ischemic stroke is a syndrome of severe neurological responses that cause neuronal death, damage to the neurovascular unit and inflammation. Notoginsenoside R1 (NG-R1) is a neuroprotective drug that is commonly used to treat neurodegenerative and cerebrovascular diseases. However, its potential mechanisms on the regulation of small molecule metabolism in ischemic stroke are largely unknown. The aim of this study was to explore the potential mechanisms of NG-R1 on the regulation of small molecule metabolism after ischemic stroke. Here, we found that NG-R1 reduced infarct size and improved neurological deficits by ameliorating neuronal damage and inhibiting glial activation in MCAO/R rats. Furthermore, using matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI), we clarified that NG-R1 regulated ATP metabolism, the tricarboxylic acid (TCA) cycle, the malate-aspartate shuttle, antioxidant activity, and the homeostasis of iron and phospholipids in the striatum and hippocampus of middle cerebral artery occlusion/reperfusion (MCAO/R) rats. In general, NG-R1 is a promising compound for brain protection from ischemic/reperfusion injury, possibly through the regulation of brain small molecule metabolism.
... Traumatic brain injury (TBI) is a serious public health problem and, at the moment, no effective clinical treatment strategies have been found. TBI indicates a sudden trauma, induced by vehicle collisions, wars, violence, terrorism, falls, or sporting activity [1]. TBI is a multiphase pathology with complex interactions between brain, periphery and the immune system [2]. ...
Traumatic brain injury (TBI) is one of the major causes of death and disability worldwide, and despite its high dissemination, effective pharmacotherapies are lacking. TBI can be divided into two phases: the instantaneous primary mechanical injury, which occurs at the moment of insult, and the delayed secondary injury, which involves a cascade of biological processes that lead to neuroinflammation. Neuroinflammation is a hallmark of both acute and chronic TBI, and it is considered to be one of the major determinants of the outcome and progression of disease. In TBI one of the emerging mechanisms for cell–cell communication involved in the immune response regulation is represented by Extracellular Vesicles (EVs). These latter are produced by all cell types and are considered a fingerprint of their generating cells. Exosomes are the most studied nanosized vesicles and can carry a variety of molecular constituents of their cell of origin, including microRNAs (miRNAs). Several miRNAs have been shown to target key neuropathophysiological pathways involved in TBI. The focus of this review is to analyze exosomes and their miRNA cargo to modulate TBI neuroinflammation providing new strategies for prevent long-term progression of disease.
... The neurovascular unit consists of neurons, neuroglia (astrocytes, microglia, and oligodendrocytes), vascular cells (pericytes, endothelial cells, and vascular smooth muscle cells) and the basal lamina matrix of brain vasculature. and gliotransmitters (Ye et al., 2003;Kardos et al., 2017;Perez et al., 2017), synthesizing glutamine, cholesterol, glutathione, and thrombospondin (Dringen et al., 2000;Slemmer et al., 2008;Colangelo et al., 2012), converting glucose into lactate (Magistretti and Pellerin, 1999;Danbolt, 2001;Magistretti, 2006), and controlling water homeostasis and neuronal activation (Lang et al., 1998;Walz, 2000;Kofuji and Newman, 2004;Jayakumar and Norenberg, 2010). Furthermore, the concentration of extracellular ions (Colangelo et al., 2012) and the glymphatic system (Jessen et al., 2015) are regulated by astrocytes. ...
Traumatic brain injury (TBI) represents one of the major causes of death worldwide and leads to persisting neurological deficits in many of the survivors. One of the most significant long-term sequelae deriving from TBI is neurodegenerative disease, which is a group of incurable diseases that impose a heavy socio-economic burden. However, mechanisms underlying the increased susceptibility of TBI to neurodegenerative disease remain elusive. The neurovascular unit (NVU) is a functional unit composed of neurons, neuroglia, vascular cells, and the basal lamina matrix. The key role of NVU dysfunction in many central nervous system diseases has been revealed. Studies have proved the presence of prolonged structural and functional abnormalities of the NVU after TBI. Moreover, growing evidence suggests impaired NVU function is also implicated in neurodegenerative diseases. Therefore, we propose the Neurovascular Unit Dysfunction (NVUD) Hypothesis, in which the persistent NVU dysfunction is thought to underlie the development of post-TBI neurodegeneration. We deduce NVUD Hypothesis through relational inference and supporting evidence, and suggest continued NVU abnormalities following TBI serve as the pathophysiological substrate and trigger yielding chronic neuroinflammation, proteinopathies and oxidative stress, consequently leading to the progression of neurodegenerative diseases. The NVUD Hypothesis may provide potential treatment and prevention strategies for TBI and late-onset neurodegenerative diseases.
... Many factors have been shown to play important roles in facilitating the development of epilepsy in humans and animal disease models, including genetic mutations, environmental factors during development, and brain injury (1)(2)(3). Although the exact mechanism of epileptogenesis is not yet fully understood, epilepsy is widely believed to be associated with an excitatory-inhibitory imbalance (4,5). There is increasing evidence in recent literature to suggest that epileptogenesis results primarily from a deficit of GABA inhibition (6,7). ...
As a main inhibitory neurotransmitter in the central nervous system, γ-aminobutyric acid (GABA) activates chloride-permeable GABAa receptors (GABAa Rs) and induces chloride ion (Cl⁻) flow, which relies on the intracellular chloride concentration ([Cl⁻]i) of the postsynaptic neuron. The Na-K-2Cl cotransporter isoform 1 (NKCC1) and the K-Cl cotransporter isoform 2 (KCC2) are two main cation-chloride cotransporters (CCCs) that have been implicated in human epilepsy. NKCC1 and KCC2 reset [Cl⁻]i by accumulating and extruding Cl⁻, respectively. Previous studies have shown that the profile of NKCC1 and KCC2 in neonatal neurons may reappear in mature neurons under some pathophysiological conditions, such as epilepsy. Although increasing studies focusing on the expression of NKCC1 and KCC2 have suggested that impaired chloride plasticity may be closely related to epilepsy, additional neuroelectrophysiological research aimed at studying the functions of NKCC1 and KCC2 are needed to understand the exact mechanism by which they induce epileptogenesis. In this review, we aim to briefly summarize the current researches surrounding the expression and function of NKCC1 and KCC2 in epileptogenesis and its implications on the treatment of epilepsy. We will also explore the potential for NKCC1 and KCC2 to be therapeutic targets for the development of novel antiepileptic drugs.
... As described above, astrocytes are considered as the main cell type responsible for the uptake of glutamate, which is metabolized later to glutamine that in turn is critical for glutamate and GABA formation inside the cell [82]. The astrocyte-controlled balance between glutamate and GABA is a critical factor in seizure occurrence [83], and is the main target of the current therapeutics. ...
The astrocytes have gained in recent decades an enormous interest as a potential target for neurotherapies, due to their essential and pleiotropic roles in brain physiology and pathology. Their precise regulation is still far from understood, although several candidate molecules/systems arise as promising targets for astrocyte-mediated neuroregulation and/or neuroprotection. The cannabinoid system and its ligands have been shown to interact and affect activities of astrocytes. Cannabidiol (CBD) is the main non-psychotomimetic cannabinoid derived from Cannabis. CBD is devoid of direct CB1 and CB2 receptor activity, but exerts a number of important effects in the brain. Here, we attempt to sum up the current findings on the effects of CBD on astrocyte activity, and in this way on central nervous system (CNS) functions, across various tested models and neuropathologies. The collected data shows that increased astrocyte activity is suppressed in the presence of CBD in models of ischemia, Alzheimer-like and Multiple-Sclerosis-like neurodegenerations, sciatic nerve injury, epilepsy, and schizophrenia. Moreover, CBD has been shown to decrease proinflammatory functions and signaling in astrocytes.
Huobahua, namely, Tripterygium hypoglaucum (Levl.) Hutch, known as a traditional Chinese herbal medicine, especially its underground parts, has been widely developed into several Tripterygium agents for the treatment of rheumatoid arthritis and other autoimmune diseases. It has sparked wide public concern about its safety, such as multi-organ toxicity. However, the toxic characteristics and damage mechanism of Huobahuagen extract (HBHGE) remain unclear. In the present study, subchronic oral toxicity study of HBHGE (10.0 g crude drug/kg/day for 12 weeks) was performed in male rats. Hematological, serum biochemical, and histopathological parameters, urinalysis, and plasma metabolic profiling were assessed. The single-dose subchronic toxicity results related to HBHGE exhibited obvious toxicity to the testis and epididymis of male rats. Furthermore, plasma metabolomics analysis suggested that a series of metabolic disorders were induced by oral administration of HBHGE, mainly focusing on amino acid (glutamate, phenylalanine, and tryptophan) metabolisms, pyrimidine metabolism, glutathione metabolism, and steroid hormone biosynthesis. Moreover, it appeared that serum testosterone in male rats treated with HBHGE for 12 weeks, decreased significantly, and was susceptible to the toxic effects of HBHGE. Taken together, conventional pathology and plasma metabolomics for preliminarily exploring subchronic toxicity and underlying mechanism can provide useful information about the reduction of toxic risks from HBHGE and new insights into the development of detoxification preparations.
Pterostilbene is a promising molecule with superior pharmacological activities and pharmacokinetic characteristics compared to its structural analogue resveratrol, which could be used to treat ischemic stroke. However, its mechanism is still unclear. The cutting-edge air flow-assisted desorption electrospray ionization mass spectrometry imaging (AFADESI-MSI) and spatial metabolomics analysis were applied to investigate the distribution of pterostilbene in ischemic rat brain and the changes of related small molecule metabolic pathways to further explore the potential mechanisms of pterostilbene against cerebral ischemia-reperfusion injury. This research found that pterostilbene could significantly restore cerebral microcirculation blood flow, reduce infarct volume, improve neurological function and ameliorate neuronal damage in ischemic rats. Moreover, pterostilbene was widely and abundantly distributed in ischemic brain tissue, laying a solid foundation for the rescue of ischemic penumbra. Further study revealed that pterostilbene played a therapeutic role in restoring energy supply, rebalancing neurotransmitters, reducing abnormal polyamine accumulation and phospholipid metabolism. These findings offer an opportunity to illustrate novel mechanisms of pterostilbene in the treatment of cerebral ischemia/reperfusion injury resulting from ischemic stroke.
The aim of the study was to evaluate the clinical value of multiple brain parameters on monitoring intracranial pressure (ICP) procedures in the therapy of severe traumatic brain injury (sTBI) utilizing mild hypothermia treatment (MHT) alone or a combination strategy with other therapeutic techniques. A total of 62 patients with sTBI (Glasgow Coma Scale score <8) were treated using mild hypothermia alone or mild hypothermia combined with conventional ICP procedures such as dehydration using mannitol, hyperventilation, and decompressive craniectomy. The multiple brain parameters, which included ICP, cerebral perfusion pressure, transcranial Doppler, brain tissue partial pressure of oxygen, and jugular venous oxygen saturation, were detected and analyzed. All of these measures can control the ICP of sTBI patients to a certain extent, but multiparameters associated with brain environment and functions have to be critically monitored simultaneously because some procedures of reducing ICP can cause side effects for long-term recovery in sTBI patients. The result suggested that multimodality monitoring must be performed during the process of mild hypothermia combined with conventional ICP procedures in order to safely target different clinical methods to specific patients who may benefit from an individual therapy.
With increasing age, the prevalence and incidence of epilepsy and seizures increases correspondingly. New-onset epilepsy in elderly people often has underlying etiology, including cerebrovascular diseases, primary neuron degenerative disorders, intracerebral tumors, and traumatic head injury. In addition, an acute symptomatic seizure cannot be called epilepsy, which manifests usually as a common symptom secondary to metabolic or toxicity factors in older people. In this review, we have mainly focused on the causes of new-onset epilepsy and seizures in elderly people. This knowledge will certainly help us to understand the reasons for high incidences of epilepsy and seizures in elderly people. We look forward to controlling epileptic seizures via the treatment of primary diseases in the future.
Stroke survivors often recover from motor deficits, either spontaneously or with the support of rehabilitative training. Since tonic GABAergic inhibition controls network excitability, it may be involved in recovery. Middle cerebral artery occlusion in rodents reduces tonic GABAergic inhibition in the structurally intact motor cortex (M1). Transcript and protein abundance of the extrasynaptic GABAA-receptor complex α4β3δ are concurrently reduced (δ-GABAARs). In vivo and in vitro analyses show that stroke-induced glutamate release activates NMDA receptors, thereby reducing KCC2 transporters and down-regulates δ-GABAARs. Functionally, this is associated with improved motor performance on the RotaRod, a test in which mice are forced to move in a similar manner to rehabilitative training sessions. As an adverse side effect, decreased tonic inhibition facilitates post-stroke epileptic seizures. Our data imply that early and sometimes surprisingly fast recovery following stroke is supported by homeostatic, endogenous plasticity of extrasynaptic GABAA receptors.
The astrocytic GLT-1 (or EAAT2) is the major glutamate transporter for clearing synaptic glutamate. While the diffusion dynamics of neurotransmitter receptors at the neuronal surface are well understood, far less is known regarding the surface trafficking of transporters in subcellular domains of the astrocyte membrane. Here, we have used live-cell imaging to study the mechanisms regulating GLT-1 surface diffusion in astrocytes in dissociated and brain slice cultures. Using GFP-time lapse imaging, we show that GLT-1 forms stable clusters that are dispersed rapidly and reversibly upon glutamate treatment in a transporter activity-dependent manner. Fluorescence recovery after photobleaching and single particle tracking using quantum dots revealed that clustered GLT-1 is more stable than diffuse GLT-1 and that glutamate increases GLT-1 surface diffusion in the astrocyte membrane. Interestingly, the two main GLT-1 isoforms expressed in the brain, GLT-1a and GLT-1b, are both found to be stabilized opposed to synapses under basal conditions, with GLT-1b more so. GLT-1 surface mobility is increased in proximity to activated synapses and alterations of neuronal activity can bidirectionally modulate the dynamics of both GLT-1 isoforms. Altogether, these data reveal that astrocytic GLT-1 surface mobility, via its transport activity, is modulated during neuronal firing, which may be a key process for shaping glutamate clearance and glutamatergic synaptic transmission.
Microglia are the main immune cells of the brain and contribute to common brain diseases. However, it is unclear how microglia influence neuronal activity and survival in the injured brain in vivo. Here we develop a precisely controlled model of brain injury induced by cerebral ischaemia combined with fast in vivo two-photon calcium imaging and selective microglial manipulation. We show that selective elimination of microglia leads to a striking, 60% increase in infarct size, which is reversed by microglial repopulation. Microglia-mediated protection includes reduction of excitotoxic injury, since an absence of microglia leads to dysregulated neuronal calcium responses, calcium overload and increased neuronal death. Furthermore, the incidence of spreading depolarization (SD) is markedly reduced in the absence of microglia. Thus, microglia are involved in changes in neuronal network activity and SD after brain injury in vivo that could have important implications for common brain diseases.
Age-related cognitive impairment has become one of the most common health threats in many countries. The biological substrate of cognition is the interconnection of neurons to form complex information processing networks. Experience-based alterations in the activities of these information processing networks lead to neuroadaptation, which is physically represented at the cellular level as synaptic plasticity. Although synaptic plasticity is known to be affected by aging, the underlying molecular mechanisms are not well described. Astrocytes, a glial cell type that is infrequently investigated in cognitive science, have emerged as energy suppliers which are necessary for meeting the abundant energy demand resulting from glutamatergic synaptic activity. Moreover, the concerted action of an astrocyte-neuron metabolic shuttle is essential for cognitive function; whereas, energetic incoordination between astrocytes and neurons may contribute to cognitive impairment. Whether altered function of the astrocyte-neuron metabolic shuttle links aging to reduced synaptic plasticity is unexplored. However, accumulated evidence documents significant beneficial effects of long-term, regular exercise on cognition and synaptic plasticity. Furthermore, exercise increases the effectiveness of astrocyte-neuron metabolic shuttle by upregulation of astrocytic lactate transporter levels. This review summarizes previous findings related to the neuronal activity-dependent astrocyte-neuron metabolic shuttle. Moreover, we discuss how aging and exercise may shape the astrocyte-neuron metabolic shuttle in cognition-associated brain areas.
Balance of excitation and inhibition is a fundamental feature of in vivo network activity and is important for its computations. However, its presence in the neocortex of higher mammals is not well established. We investigated the dynamics of excitation and inhibition using dense multielectrode recordings in humans and monkeys. We found that in all states of the wake-sleep cycle, excitatory and inhibitory ensembles are well balanced, and co-fluctuate with slight instantaneous deviations from perfect balance, mostly in slow-wave sleep. Remarkably, these correlated fluctuations are seen for many different temporal scales. The similarity of these computational features with a network model of self-generated balanced states suggests that such balanced activity is essentially generated by recurrent activity in the local network and is not due to external inputs. Finally, we find that this balance breaks down during seizures, where the temporal correlation of excitatory and inhibitory populations is disrupted. These results show that balanced activity is a feature of normal brain activity, and break down of the balance could be an important factor to define pathological states.
Along the last years it has been demonstrated that non-neural cells play a major role in the pathogenesis of the Primary Degenerative Disorders (PDD) of the human central nervous system. Among them, astrocytes coordinate and participate in many different and complex metabolic processes, in close interaction with neurons. Moreover, increasing experimental evidence hints an early astrocytic dysfunction in these diseases. In this mini review we summarize the astrocytic behavior in PDDs, with special consideration to the experimental observations where astrocytic pathology precedes the development of neuronal dysfunction. We also suggest a different approach that could be consider in human investigations in Alzheimer’s and Parkinson's disease. We believe that the study of PDDs with human brain samples may hold the key of a paradigmatic physiopathological process in which astrocytes might be the main players.
Historically, glial cells have been recognized as a structural component of the brain. However, it has become clear that glial cells are intimately involved in the complexities of neural networks and memory formations. Astrocytes, microglia, and oligodendrocytes have dynamic responsibilities which substantially impact neuronal function and activities. Moreover, the importance of glia following brain injury has come to the forefront in discussions to improve axonal regeneration and functional recovery. The numerous activities of glia following injury can either promote recovery or underlie the pathobiology of memory deficits. This review outlines the pathological states of glial cells which evolve from their positive supporting roles to those which disrupt synaptic function and neuroplasticity following injury. Evidence suggests that glial cells interact extensively with neurons both chemically and physically, reinforcing their role as pivotal for higher brain functions such as learning and memory. Collectively, this mini review surveys investigations of how glial dysfunction following brain injury can alter mechanisms of synaptic plasticity and how this may be related to an increased risk for persistent memory deficits. We also include recent findings that demonstrate new molecular avenues for clinical biomarker discovery.
Glutamate (Glu) plays a key role in excitotoxicity-related injury in cerebral ischemia. In the brain, Glu homeostasis depends on Glu transporters, including the excitatory amino acid transporters and the cysteine/Glu antiporter (xc-). We hypothesized that drugs acting on Glu transporters, such as ceftriaxone (CEF, 200 mg/kg, i.p.) and N-acetylcysteine (NAC, 150 mg/kg, i.p.), administered repeatedly for 5 days before focal cerebral ischemia in rats and induced by a 90-min middle cerebral artery occlusion (MCAO), may induce brain tolerance to ischemia. We compared the effects of these drugs on brain infarct volume, neurological deficits and the mRNA and protein expression of the Glu transporter-1 (GLT-1) and xc- with the effects of ischemic preconditioning and chemical preconditioning using 3-nitropropionic acid. Administration of CEF and NAC significantly reduced infarct size and neurological deficits caused by a 90-min MCAO. These beneficial effects were accompanied by changes in GLT-1 expression caused by a 90-min MCAO at both the mRNA and protein levels in the frontal cortex, hippocampus, and dorsal striatum. Thus, the results of this study suggest that the regulation of GLT-1 and xc- plays a role in the development of cerebral tolerance to ischemia and that this regulation may be a novel approach in the therapy of brain ischemia.
Biology is full of instances of exaptation, the functional shift or co-optation of a trait during evolution (Gould and Vrba, 1982). Exaptation played a critical role in human brain evolution. For example, hominin brain expansion is thought to have happened opportunistically upon food resources rich in brain-selective nutrients (Tattersall, 2010). Prehensile hands and bipedalism were other enabling factors in this process, as both features preceded the expansion of the brain, and notably, the development and utilization of tools (Wood, 2010). Similarly, central and peripheral vocal structures, initially used for a variety of non-linguistic reasons (chewing, larynx protection, size exaggeration), were pre-existing conditions to, and provided the anatomical basis for, the evolution of language (e.g., MacNeilage, 2010). The very emergence of abstract cognitive abilities in humans are hypothesized to have evolved from faculties originally developed for other purposes (Pinker, 2010).
The discovery that transient elevations of calcium concentration occur in astrocytes, and release 'gliotransmitters' which act on neurons and vascular smooth muscle, led to the idea that astrocytes are powerful regulators of neuronal spiking, synaptic plasticity and brain blood flow. These findings were challenged by a second wave of reports that astrocyte calcium transients did not mediate functions attributed to gliotransmitters and were too slow to generate blood flow increases. Remarkably, the tide has now turned again: the most important calcium transients occur in fine astrocyte processes not resolved in earlier studies, and new mechanisms have been discovered by which astrocyte [Ca(2+)]i is raised and exerts its effects. Here we review how this third wave of discoveries has changed our understanding of astrocyte calcium signaling and its consequences for neuronal function.
Astrocytes are housekeepers of the central nervous system (CNS) and are important for CNS development, homeostasis and defence. They communicate with neurones and other glial cells through the release of signalling molecules. Astrocytes secrete a wide array of classic neurotransmitters, neuromodulators and hormones, as well as metabolic, trophic and plastic factors, all of which contribute to the gliocrine system. The release of neuroactive substances from astrocytes occurs through several distinct pathways that include diffusion through plasmalemmal channels, translocation by multiple transporters and regulated exocytosis. As in other eukaryotic cells, exocytotic secretion from astrocytes involves divergent secretory organelles (synaptic-like microvesicles, dense-core vesicles, lysosomes, exosomes and ectosomes), which differ in size, origin, cargo, membrane composition, dynamics and functions. In this review, we summarize the features and functions of secretory organelles in astrocytes. We focus on the biogenesis and trafficking of secretory organelles and on the regulation of the exocytotic secretory system in the context of healthy and diseased astrocytes.
Since it was discovered, the citric acid cycle has been known to be central to cell metabolism and energy homeostasis. Mainly found in the mitochondrial matrix, some of the intermediates of the Krebs cycle are also present in the blood stream. Currently, there are several reports that indicate functional roles for Krebs intermediates out of its cycle. Succinate, for instance, acts as an extracellular ligand by binding to a G-protein coupled receptor, known as GPR91, expressed in kidney, liver, heart, retinal cells and possibly many other tissues, leading to a wide array of physiological and pathological effects. Through GPR91, succinate is involved in functions such as regulation of blood pressure, inhibition of lipolysis in white adipose tissue, development of retinal vascularization, cardiac hypertrophy and activation of stellate hepatic cells by ischemic hepatocytes. Along the current review, these new effects of succinate through GPR91 will be explored and discussed.
Astrocytes are important for normal brain functioning. Astrocytes are metabolic regulators of the brain that exert many functions such as the preservation of blood–brain barrier (BBB) function, clearance of toxic substances, and generation of antioxidant molecules and growth factors. These functions are fundamental to sustain the function and survival of neurons and other brain cells. For these reasons, the protection of astrocytes has become relevant for the prevention of neuronal death during brain pathologies such as Parkinson’s disease, Alzheimer’s disease, stroke, and other neurodegenerative conditions. Currently, different strategies are being used to protect the main astrocytic functions during neurological diseases, including the use of growth factors, steroid derivatives, mesenchymal stem cell paracrine factors, nicotine derivatives, and computational biology tools. Moreover, the combined use of experimental approaches with bioinformatics tools such as the ones obtained through system biology has allowed a broader knowledge in astrocytic protection both in normal and pathological conditions. In the present review, we highlight some of these recent paradigms in assessing astrocyte protection using experimental and computational approaches and discuss how they could be used for the study of restorative therapies for the brain in pathological conditions.
Both acute and chronic stress profoundly affect hippocampally-dependent learning and memory: moderate stress generally enhances, while chronic or extreme stress can impair, neural and cognitive processes. Within the brain, stress elevates both norepinephrine and glucocorticoids, and both affect several genomic and signaling cascades responsible for modulating memory strength. Memories formed at times of stress can be extremely strong, yet stress can also impair memory to the point of amnesia. Often overlooked in consideration of the impact of stress on cognitive processes, and specifically memory, is the important contribution of glia as a target for stress-induced changes. Astrocytes, microglia, and oligodendrocytes all have unique contributions to learning and memory. Furthermore, these three types of glia express receptors for both norepinephrine and glucocorticoids and are hence immediate targets of stress hormone actions. It is becoming increasingly clear that inflammatory cytokines and immunomodulatory molecules released by glia during stress may promote many of the behavioral effects of acute and chronic stress. In this review, the role of traditional genomic and rapid hormonal mechanisms working in concert with glia to affect stress-induced learning and memory will be emphasized.
Glial cells, and in particular astrocytes, are crucial to maintain neuronal microenvironment by regulating energy metabolism, neurotransmitter uptake, gliotransmission, and synaptic development. Moreover, a typical feature of astrocytes is their high expression level of connexins, a family of membrane proteins that form gap junction channels allowing intercellular exchanges and hemichannels that provide release and uptake pathways for neuroactive molecules. Interestingly, several studies have revealed unexpected changes in astrocytes from depressive patients and rodent models of depressive-like behavior. Moreover, changes in the expression level of the astroglial connexin 43 (Cx43) have been reported in a depressive context. On the other hand, antidepressive drugs have also been shown to impact the expression of this connexin in astrocytes. However, so far there is little information concerning the functional consequence of these changes, i.e., the status of gap junctional communication and hemichannel activity in astrocytes exposed to antidepressants. In the present work we focused our attention on the action of seven antidepressants from four different therapeutic classes and tested their effects on Cx43 expression and on the two connexin-based channels functions studied in cultured astrocytes. We here report that when used at non-toxic and clinically relevant concentrations they have no effects on Cx43 expression but differential effects on Cx43 gap junction channels. Moreover, all tested antidepressants inhibit Cx43 hemichannel with different efficiency depending on their therapeutic classe. By studying the impact of antidepressants on the functional status of astroglial connexin channels, contributing to dynamic neuroglial interactions, our observations should help to better understand the mechanism by which these drugs provide their effect in the brain.
Recent studies combining pharmacological, behavioral, electrophysiological and molecular approaches indicate that depression results from maladaptive neuroplastic processing occurring in defined frontolimbic circuits responsible for emotional processing such as the prefrontal cortex, hippocampus, amygdala and ventral striatum. However, the exact mechanisms controlling synaptic plasticity that are disrupted to trigger depressive conditions have not been elucidated. Since glial cells (astrocytes and microglia) tightly and dynamically interact with synapses, engaging a bi-directional communication critical for the processing of synaptic information, we now revisit the role of glial cells in the etiology of depression focusing on a dysfunction of the ‘quad-partite’ synapse. This interest is supported by the observations that depressive-like conditions are associated with a decreased density and hypofunction of astrocytes and with an increase microglia ‘activation’ in frontolimbic regions, which is expected to contribute for the synaptic dysfunction present in depression. Furthermore, the traditional culprits of depression (glucocorticoids, biogenic amines, BDNF) affect glia functioning, whereas antidepressant treatments (SSRIs, electroshock, deep brain stimulation) recover glia functioning. In this context of a quad-partite synapse, systems modulating glia-synapse bidirectional communication - such as the purinergic neuromodulation system operated by ATP and adenosine - emerge as promising candidates to “re-normalize” synaptic function by combining direct synaptic effects with an ability to also control astrocyte and microglia function. This proposed triple action of purines to control aberrant synaptic function illustrates the rationale to consider the interference with glia dysfunction as a mechanism of action driving the design of future pharmacological tools to manage depression.
Mental illnesses have long been perceived as the exclusive consequence of abnormalities in neuronal functioning. Until recently, the role of glial cells in the pathophysiology of mental diseases has largely been overlooked. However recently, multiple lines of evidence suggest more diverse and significant functions of glia with behavior-altering effects. The newly ascribed roles of astrocytes, oligodendrocytes and microglia have led to their examination in brain pathology and mental illnesses. Indeed, abnormalities in glial function, structure and density have been observed in postmortem brain studies of subjects diagnosed with mental illnesses. In this review, we discuss the newly identified functions of glia and highlight the findings of glial abnormalities in psychiatric disorders. We discuss these preclinical and clinical findings implicating the involvement of glial cells in mental illnesses with the perspective that these cells may represent a new target for treatment.
The neurone-centred view of the past disregarded or downplayed the role of astroglia as a primary component in the pathogenesis of neurological diseases. As this concept is changing, so is also the perceived role of astrocytes in the healthy and diseased brain and spinal cord. We have started to unravel the different signalling mechanisms that trigger specific molecular, morphological and functional changes in reactive astrocytes that are critical for repairing tissue and maintaining function in CNS pathologies, such as neurotrauma, stroke, or neurodegenerative diseases. An increasing body of evidence shows that the effects of astrogliosis on the neural tissue and its functions are not uniform or stereotypic, but vary in a context-specific manner from astrogliosis being an adaptive beneficial response under some circumstances to a maladaptive and deleterious process in another context. There is a growing support for the concept of astrocytopathies in which the disruption of normal astrocyte functions, astrodegeneration or dysfunctional/maladaptive astrogliosis are the primary cause or the main factor in neurological dysfunction and disease. This review describes the multiple roles of astrocytes in the healthy CNS, discusses the diversity of astroglial responses in neurological disorders and argues that targeting astrocytes may represent an effective therapeutic strategy for Alexander disease, neurotrauma, stroke, epilepsy and Alzheimer's disease as well as other neurodegenerative diseases.
Lead intoxication in humans is characterized by cognitive impairments, particularly in the domain of memory, where evidence indicates that glutamatergic neurotransmission may be impacted. Animal and cell culture studies have shown that lead decreases the expression and activity of glutamine synthetase (GS) in astrocytes, yet the basis of this effect is uncertain. To investigate the mechanism responsible, the present study exposed primary astrocyte cultures to a range of concentrations of lead acetate (0–330 μM) for up to 24 h. GS activity was significantly reduced in cells following 24 h incubation with 100 or 330 μM lead acetate. However, no reduction in GS activity was detected when astrocytic lysates were co-incubated with lead acetate, suggesting that the mechanism is not due to a direct interaction and involves intact cells. Since GS is highly sensitive to oxidative stress, the capacity of lead to inhibit the clearance of hydrogen peroxide (H2O2) was investigated. It was found that exposure to lead significantly diminished the capacity of astrocytes to degrade H2O2, and that this was due to a reduction in the effectiveness of the glutathione system, rather than to catalase. These results suggest that the inhibition of GS activity in lead poisoning is a consequence of slowed H2O2 clearance, and supports the glutathione pathway as a primary therapeutic target.
It is fast emerging that maintaining mitochondrial function is important for regulating astrocyte function, although the specific mechanisms that govern astrocyte mitochondrial trafficking and positioning remain poorly understood. The mitochondrial Rho-GTPase 1 protein (Miro1) regulates mitochondrial trafficking and detachment from the microtubule transport network to control activity-dependent mitochondrial positioning in neurons. However, whether Miro proteins are important for regulating signaling-dependent mitochondrial dynamics in astrocytic processes remains unclear. Using live-cell confocal microscopy of rat organotypic hippocampal slices, we find that enhancing neuronal activity induces transient mitochondrial remodeling in astrocytes, with a concomitant, transient reduction in mitochondrial trafficking, mediated by elevations in intracellular Ca2+. Stimulating neuronal activity also induced mitochondrial confinement within astrocytic processes in close proximity to synapses. Furthermore, we show that the Ca2+-sensing EF-hand domains of Miro1 are important for regulating mitochondrial trafficking in astrocytes and required for activity-driven mitochondrial confinement near synapses. Additionally, activity-dependent mitochondrial positioning by Miro1 reciprocally regulates the levels of intracellular Ca2+in astrocytic processes. Thus, the regulation of intracellular Ca2+ signaling, dependent on Miro1-mediated mitochondrial positioning, could have important consequences for astrocyte Ca2+ wave propagation, gliotransmission, and ultimately neuronal function.
An imbalance between excitatory (E) glutamate and inhibitory (I) GABA transmission may underlie neurodevelopmental conditions such as Autism Spectrum Disorder (ASD) and schizophrenia. This may be direct, through alterations in synaptic genes, but there is increasing evidence for the importance of indirect modulation of E/I balance through glial mechanisms. Here we used C57BL/6J mice to test the hypothesis that E/I balance can be shifted by N-acetylcysteine (NAC), which acts at the cystine-glutamate antiporter of glial cells. Striatal glutamate was quantified in-vivo using proton magnetic resonance spectroscopy. The effect of NAC on behaviours relevant to ASD was examined in a separate cohort. NAC induced a time-dependent decrease in striatal glutamate, which recapitulated findings of lower striatal glutamate reported in ASD. NAC-treated animals were significantly less active and more ‘anxious’ in the open field test; and NAC-treated females had significantly impaired prepulse inhibition of startle response. This at least partly mimics greater anxiety and impaired sensorimotor gating reported in neurodevelopmental disorders. Thus glial mechanisms regulate E/I balance acutely and have functional consequences. Glial cells may be a potential drug target for the development of new therapies for neurodevelopmental disorders.
Astrocytes, the most heterogeneous glial cells in the central nervous system (CNS), execute a multitude of homeostatic functions and contribute to memory formation. Consolidation of synaptic and systemic memory is a prolonged process and hours are required to form long-term memory. In the past, neurons or their parts have been considered to be the exclusive cellular sites of these processes, however, it has now become evident that astrocytes provide an important and essential contribution to memory formation. Astrocytes participate in the morphological remodeling associated with synaptic plasticity, an energy-demanding process that requires mobilization of glycogen, which, in the CNS, is almost exclusively stored in astrocytes. Synaptic remodeling also involves bidirectional astroglial-neuronal communication supported by astroglial receptors and release of gliosignaling molecules. Astroglia exhibit cytoplasmic excitability that engages second messengers, such as Ca2+, for phasic, and cyclic adenosine monophosphate (cAMP), for tonic signal coordination with neuronal processes. The detection of signals by astrocytes and the release of gliosignaling molecules, in particular by vesicle-based mechanisms, occurs with a significant delay after stimulation, orders of magnitude longer than that present in stimulus–secretion coupling in neurons. These particular arrangements position astrocytes as integrators ideally tuned to support time-dependent memory formation.
Pathological remodelling of astroglia represents an important component of the pathogenesis of Alzheimer's disease (AD). In AD astrocytes undergo both atrophy and reactivity; which may be specific for different stages of the disease evolution. Astroglial reactivity represents the generic defensive mechanism, and inhibition of astrogliotic response exacerbates b-amyloid pathology associated with AD. In animal models of AD astroglial reactivity is different in different brain regions, and the deficits of reactive response observed in entorhinal and prefrontal cortices may be linked to their vulnerability to AD progression. Reactive astrogliosis is linked to astroglial Ca2+ signalling, this latter being widely regarded as a mechanism of astroglial excitability. The AD pathology evolving in animal models as well as acute or chronic exposure to -amyloid induce pathological remodelling of Ca2+ signalling toolkit in astrocytes. This remodelling modifies astroglial Ca2+ signalling and may be linked to cellular mechanisms of AD pathogenesis.
Unlabelled:
We recently showed that inhibition of neuronal activity, glutamate uptake, or reversed-Na(+)/Ca(2+)-exchange with TTX, TFB-TBOA, or YM-244769, respectively, increases mitochondrial mobility in astrocytic processes. In the present study, we examined the interrelationships between mitochondrial mobility and Ca(2+) signaling in astrocyte processes in organotypic cultures of rat hippocampus. All of the treatments that increase mitochondrial mobility decreased basal Ca(2+). As recently reported, we observed spontaneous Ca(2+) spikes with half-lives of ∼1 s that spread ∼6 μm and are almost abolished by a TRPA1 channel antagonist. Virtually all of these Ca(2+) spikes overlap mitochondria (98%), and 62% of mitochondria are overlapped by these spikes. Although tetrodotoxin, TFB-TBOA, or YM-244769 increased Ca(2+) signaling, the specific effects on peak, decay time, and/or frequency were different. To more specifically manipulate mitochondrial mobility, we explored the effects of Miro motor adaptor proteins. We show that Miro1 and Miro2 are both expressed in astrocytes and that exogenous expression of Ca(2+)-insensitive Miro mutants (KK) nearly doubles the percentage of mobile mitochondria. Expression of Miro1(KK) had a modest effect on the frequency of these Ca(2+) spikes but nearly doubled the decay half-life. The mitochondrial proton ionophore, FCCP, caused a large, prolonged increase in cytosolic Ca(2+) followed by an increase in the decay time and the spread of the spontaneous Ca(2+) spikes. Photo-ablation of mitochondria in individual astrocyte processes has similar effects on Ca(2+). Together, these studies show that Ca(2+) regulates mitochondrial mobility, and mitochondria in turn regulate Ca(2+) signals in astrocyte processes.
Significance statement:
In neurons, the movement and positioning of mitochondria at sites of elevated activity are important for matching local energy and Ca(2+) buffering capacity. Previously, we demonstrated that mitochondria are immobilized in astrocytes in response to neuronal activity and glutamate uptake. Here, we demonstrate a mechanism by which mitochondria are immobilized in astrocytes subsequent to increases in intracellular [Ca(2+)] and provide evidence that mitochondria contribute to the compartmentalization of spontaneous Ca(2+) signals in astrocyte processes. Immobilization of mitochondria at sites of glutamate uptake in astrocyte processes provides a mechanism to coordinate increases in activity with increases in mitochondrial metabolism.
Objectives
GEBR-7b, a potential phosphodiesterase 4D inhibitor, has been shown to have memory-enhancing effects in rodents. However, it is still unknown whether GEBR-7b also has the antidepressant-like effects in rats. Herein, we examined the potential of GEBR-7b to attenuate depression-like behaviors in the rat model of depression induced by chronic unpredictable stress (CUS). Next, we also investigated the alterations of cyclic adenosine monophosphate (cAMP), protein kinase A (PKA) catalytic subunit (PKAca), cAMP response element-binding (CREB), and glutamate transporter 1 (GLT1) levels produced by GEBR-7b in the rats model of depression.
Methods
Effects of GEBR-7b on CUS (35 days)-induced depression-like behaviors were examined by measuring immobility time in the forced swimming test (FST). Hippocampal cAMP levels were examined by enzyme-linked immunosorbent assay, whereas PKAca, phosphorylation of CREB (pCREB), CREB, and GLT1 in the hippocampus of rats were subjected to Western blot analysis.
Results
CUS exposure caused a depression-like behavior evidenced by the increased immobility time in FST. Depression-like behavior induced by CUS was accompanied by a significant increased GLT, decreased cAMP, PKAca, pCREB activities in hippocampus. However, repeated GEBR-7b administration significantly reversed CUS-induced depression-like behavior and changes of cAMP/PKA/CREB/GLT1 signaling. No alteration was observed in locomotor activity in open field test.
Conclusion
These findings indicate that GEBR-7b reversed the depression-like behaviors induced by CUS in rats, which is at least in part mediated by modulating cAMP, PKAca, pCREB, and GLT1 levels in the hippocampus of rats, supporting its neuroprotective potential against behavioral and biochemical dysfunctions induced by CUS.
Karen A Nolan, Carsten C ScholzInstitute of Physiology, University of Zürich, Zürich, SwitzerlandAbstract: In May 2015, the hypoxia research community came together at the largest meeting in this field to date, to present and discuss their most recent and mainly unpublished findings. This meeting report aims to summarize the data presented at this conference, which were broadly separated into the areas of the cellular hypoxic response, the relevance of the hypoxic response in health and disease, and the development of new therapeutics targeting the hypoxic response.Keywords: hydroxylase, HIF, PHD, FIH, oxygen, hydroxylase inhibitor
Synaptic dysfunction is a hallmark of many neurodegenerative and psychiatric brain disorders, yet we know little about the mechanisms that underlie synaptic vulnerability. Although neuroinflammation and reactive gliosis are prominent in virtually every CNS disease, glia are largely viewed as passive responders to neuronal damage rather than drivers of synaptic dysfunction. This perspective is changing with the growing realization that glia actively signal with neurons and influence synaptic development, transmission and plasticity through an array of secreted and contact-dependent signals. We propose that disruptions in neuron-glia signaling contribute to synaptic and cognitive impairment in disease. Illuminating the mechanisms by which glia influence synapse function may lead to the development of new therapies and biomarkers for synaptic dysfunction.
The Na(+) -dependent glutamate transporter, GLT-1 (EAAT2), shows selective expression in astrocytes, and neurons induce expression of GLT-1 in astrocytes. In unpublished analyses of GLT-1 promoter reporter mice, we identified an evolutionarily conserved domain of 467 nucleotides ~8 kb upstream of the GLT-1 translation start site that is required for astrocytic expression. Using in silico approaches, we identified Pax6 as a transcription factor that could contribute to the control of GLT-1 expression by binding within this region. We demonstrated expression of Pax6 protein in astrocytes in vivo. Lentiviral transduction of astrocytes with exogenous Pax6 increased expression of enhanced green fluorescent protein (eGFP) in astrocytes prepared from transgenic mice that use a bacterial artificial chromosome (BAC) containing a large genomic region surrounding the GLT-1 gene to control expression of eGFP. It also increased GLT-1 protein, and GLT-1-mediated activity, while there was no effect on the levels of astroglial glutamate transporter, GLAST. Transduction of astrocytes with an shRNA directed against Pax6 reduced neuron-dependent induction of GLT-1 or eGFP. Finally, we confirmed Pax6 interaction with the predicted DNA binding site in electrophoretic mobility assays (EMSA) and chromatin immunoprecipitation (ChIP). Together, these studies show that Pax6 contributes to regulation of GLT-1 through an interaction with these distal elements and identify a novel role of Pax6 in astrocyte biology. This article is protected by copyright. All rights reserved.
Astrocytes represent a highly heterogeneous population of neural cells primarily responsible for the homeostasis of the CNS. Astrocytes express multiple receptors for neurotransmitters, including the serotonin 5-HT2B receptors and interact with neurones at the synapse. Astroglia contribute to neurological diseases through homeostatic response, neuroprotection and reactivity. In major depression, astrocytes show signs of degeneration and are decreased in numbers, which may lead to a misbalance in neurotransmission and aberrant synaptic connectivity. In this review, we summarize astroglia-specific effects of major antidepressants and outline future strategies for astroglia-specific therapy in neuropsychiatric disorders.
Parkinson’s disease (PD) is a chronic, progressive, and the second most common form of neurodegenerative disorders. In order to explore novel agents for the treatment of PD, in the current study, we have evaluated the neuroprotective efficacy of ferulic acid (FA) using rotenone (ROT)-induced rat model of PD. ROT was administered 2.5 mg/kg body weight to male Wistar rats for 4 weeks to induce the PD. Since PD is progressive and chronic in nature, the paradigm for evaluating FA was based on chronic administration for 4 weeks at the dose of 50 mg/kg, 30 minutes prior to ROT administration. ROT administration caused significant reduction in endogenous antioxidants such as superoxide dismutase, catalase, and glutathione. ROT challenge-induced lipid peroxidation evidenced by increased malondialdehyde following perturbation of antioxidant defense. Apart from oxidative stress, ROT also activated proinflammatory cytokines and enhanced inflammatory mediators such as cyclooxygenase-2 and inducible nitric oxide synthase. The immunofluorescence analysis revealed a significant increase in the number of activated microglia and astrocytes accompanied by a significant loss of dopamine (DA) neurons in the substantia nigra pars compacta area upon ROT injection. However, treatment with FA rescued DA neurons in substantia nigra pars compacta area and nerve terminals in the striatum from the ROT insult. FA treatment also restored antioxidant enzymes, prevented depletion of glutathione, and inhibited lipid peroxidation. Following treatment with FA, the inflammatory mediators such as cyclooxygenase-2 and inducible nitric oxide synthase and proinflammatory cytokines were also reduced. Further, the results were supported by a remarkable reduction of Iba-1 and GFAP hyperactivity clearly suggests attenuation of microglial and astrocytic activation. Results of our study suggest that FA has promising neuroprotective effect against degenerative changes in PD, and the protective effects are mediated through its antioxidant and anti-inflammatory properties.
Glucose, the main energy substrate used in the CNS, is continuously supplied by the periphery. Glutamate, the major excitatory neurotransmitter, is foreseen as a complementary energy contributor in the brain. In particular, astrocytes actively take up glutamate and may use it through oxidative glutamate dehydrogenase (GDH) activity. Here, we investigated the significance of glutamate as energy substrate for the brain. Upon glutamate exposure, astrocytes generated ATP in a GDH-dependent way. The observed lack of glutamate oxidation in brain-specific GDH null CnsGlud1(-/-) mice resulted in a central energy-deprivation state with increased ADP/ATP ratios and phospho-AMPK in the hypothalamus. This induced changes in the autonomous nervous system balance, with increased sympathetic activity promoting hepatic glucose production and mobilization of substrates reshaping peripheral energy stores. Our data reveal the importance of glutamate as necessary energy substrate for the brain and the role of central GDH in the regulation of whole-body energy homeostasis.
An imbalance between excitatory (E) glutamate and inhibitory (I) GABA transmission may underlie neurodevelopmental conditions such as autism spectrum disorder (ASD) and schizophrenia. This may be direct, through alterations in synaptic genes, but there is increasing evidence for the importance of indirect modulation of E/I balance through glial mechanisms. Here, we used C57BL/6J mice to test the hypothesis that striatal glutamate levels can be shifted by N-acetylcysteine (NAC), which acts at the cystine-glutamate antiporter of glial cells. Striatal glutamate was quantified in vivo using proton magnetic resonance spectroscopy. The effect of NAC on behaviors relevant to ASD was examined in a separate cohort. NAC induced a time-dependent decrease in striatal glutamate, which recapitulated findings of lower striatal glutamate reported in ASD. NAC-treated animals were significantly less active and more anxious in the open field test; and NAC-treated females had significantly impaired prepulse inhibition of startle response. This at least partly mimics greater anxiety and impaired sensorimotor gating reported in neurodevelopmental disorders. Thus glial mechanisms regulate glutamate acutely and have functional consequences even in adulthood. Glial cells may be a potential drug target for the development of new therapies for neurodevelopmental disorders across the life-span.
Simulation-based research has become possible and has replaced experiments in several sciences when critical mass is reached in experimental data and computing power. In life science in general, and in neuroscience in particular, both data and computing requirements are however extreme. The Blue Brain Project is pioneering a strategy to build a facility that can absorb biological data and drive the computing needs that would support simulation-based research for brain research. The first challenge in the project was to database, reconstruct, simulate, visualize and analyze a neocortical column of a 2 week old somatosensory rat cortex at cellular level precision. The facility now allows the building of the neocortical column (and any detailed neural models) according to biological specifications and is designed to allow continual refinement of the biological accuracy. The process of building the model column has exposed fundamental principles of circuit design and operation that were not known before and the models can be used to replicate experiments and explore in silico far beyond the technological limitations imposed on experiments in order to make predictions for future experiments. The next phase of the project aims to allow biological refinement down to the molecular level and to expand the facility to allow whole-brain simulation-based research. The rapid increase in computational power and increased volume and quality of data representations of biological processes will allow progressively deeper exploration of the complexity of the brain and more detailed hypothesis testing. We conclude that simulation-based research is a viable new approach to understanding the structure, function and dysfunctions of the brain.
Ketamine is an anesthetic that exhibits analgesic, psychotomimetic, and rapid antidepressant effects that are of particular neuropharmacological interest. Recent studies revealed astrocytic Ca ²⁺ signaling and regulated exocytosis as ketamine‐targeted processes. Thus high‐resolution cell‐attached membrane capacitance measurements were performed to examine the influence of ketamine on individual vesicle interactions with the plasma membrane in cultured rat astrocytes. Ketamine evoked long‐lasting bursts of repetitive opening and closing of the fusion pore that were both time‐ and concentration‐dependent. Moreover, acute application and subanesthetic doses of ketamine elicited a significant increase in the occurrence of bursts that were characterized by a decreased fusion pore conductance, indicating that the fusion pore was stabilized in a narrow configuration. The time‐ and concentration‐dependent increase in burst occurrence was correlated with a decrease in full fission events. This study has demonstrated a novel effect of ketamine manifested as stabilization of a fusion pore incapable of transiting to full vesicle fission, suggestive of an inhibitory effect on vesicle retrieval. This until now unrecognized effect of ketamine on the vesicle fusion pore might play a role in astroglial release and (re)uptake of molecules, modulating synaptic activity.
image This study demonstrates a novel effect of ketamine on the fusion pore. High‐resolution cell‐attached membrane capacitance measurements revealed that ketamine evokes long‐lasting flickering of a narrow fusion pore that is incapable of transiting to full fission. Astrocytic vesicle fusion/retrieval modified by subanesthetic ketamine doses most likely affects gliotransmission and indicates a non‐neuronal mechanism of ketamine action that may contribute to its behavioral effects.
Peri-infarct opening of the blood–brain barrier may be associated with spreading depolarizations, seizures, and epileptogenesis as well as cognitive dysfunction. We aimed to investigate the mechanisms underlying neural network pathophysiology in the blood–brain barrier-dysfunctional hippocampus. Photothrombotic stroke within the rat neocortex was associated with increased intracranial pressure, vasogenic edema, and peri-ischemic blood–brain barrier dysfunction that included the ipsilateral hippocampus. Intrahippocampal recordings revealed electrographic seizures within the first week in two-thirds of animals, accompanied by a reduction in gamma and increase in theta frequency bands. Synaptic interactions were studied in parasagittal hippocampal slices at 24 h and seven days post-stroke. Field potential recordings in CA1 and CA3 uncovered multiple population spikes, epileptiform episodes, and spreading depolarizations at 24 h. Input–output analysis revealed that fEPSP-spike coupling was significantly enhanced at seven days. In addition, CA1 feedback and feedforward inhibition were diminished. Slices generating epileptiform activity at seven days revealed impaired bidirectional long-term plasticity following high and low-frequency stimulation protocols. Microarray and PCR data confirmed changes in expression of astrocyte-related genes and suggested downregulation in expression of GABAA-receptor subunits. We conclude that blood-brain barrier dysfunction in the peri-infarct hippocampus is associated with early disinhibition, hyperexcitability, and abnormal synaptic plasticity.
Tibolone, a synthetic steroid used for the prevention of osteoporosis and the treatment of climacteric symptoms in post-menopausal women, may exert tissue selective estrogenic actions acting on estrogen receptors (ERs). We previously showed that tibolone protects human T98G astroglial cells against glucose deprivation (GD). In this study we have explored whether the protective effect of tibolone on these cells is mediated by ERs. Experimental studies showed that both ERα and ERβ were involved in the protection by tibolone on GD cells, being ERβ preferentially involved on these actions over ERα. Tibolone increased viability of GD cells by a mechanism fully blocked by an ERβ antagonist and partially blocked by an ERα antagonist. Furthermore, ERβ inhibition prevented the effect of tibolone on nuclear fragmentation, ROS and mitochondrial membrane potential in GD cells. The protective effect of tibolone was mediated by neuroglobin. Tibolone upregulated neuroglobin in T98G cells and primary mouse astrocytes by a mechanism involving ERβ and neuroglobin silencing prevented the protective action of tibolone on GD cells. In summary, tibolone protects T98G cells by a mechanism involving ERβ and the upregulation of neuroglobin.
Transected axons fail to regrow in the mature central nervous system. Astrocytic scars are widely regarded as causal in this failure. Here, using three genetically targeted loss-of-function manipulations in adult mice, we show that preventing astrocyte scar formation, attenuating scar-forming astrocytes, or ablating chronic astrocytic scars all failed to result in spontaneous regrowth of transected corticospinal, sensory or serotonergic axons through severe spinal cord injury (SCI) lesions. By contrast, sustained local delivery via hydrogel depots of required axon-specific growth factors not present in SCI lesions, plus growth-activating priming injuries, stimulated robust, laminin-dependent sensory axon regrowth past scar-forming astrocytes and inhibitory molecules in SCI lesions. Preventing astrocytic scar formation significantly reduced this stimulated axon regrowth. RNA sequencing revealed that astrocytes and non-astrocyte cells in SCI lesions express multiple axon-growth-supporting molecules. Our findings show that contrary to the prevailing dogma, astrocyte scar formation aids rather than prevents central nervous system axon regeneration.
After spinal-cord injury, cells called astrocytes form a scar that is thought to block neuronal regeneration. The finding that the scar promotes regrowth of long nerve projections called axons challenges this long-held dogma. See Article p.195
Background:
Water-soluble components in mesenteric lymph have been implicated in the pathophysiology of acute lung injury and distal organ failure following trauma and haemorrhagic shock. Proteomics analyses have recently shown similarities and specificities of post-trauma/haemorrhagic shock lymph and plasma. We hypothesise that the metabolic phenotype of post-trauma/haemorrhagic shock mesenteric lymph and plasma share common metabolites, but are also characterised by unique features that differentiate these two fluids.
Materials and methods:
Matched samples were collected from 5 brain-dead organ donors who had suffered extreme trauma/haemorrhagic shock. Metabolomics analyses were performed through ultra-high performance liquid chromatography mass spectrometry.
Results:
Overall, 269 metabolites were identified in either fluid. Despite significant overlapping, metabolic phenotypes of matched lymph or plasma from the same patients could be used to discriminate sample fluid or biological patient/traumatic-injury origin. Metabolites showing relatively high levels in both fluids included markers of haemolysis and cell lysis secondary to tissue injury.
Discussion:
High positive correlations were observed between the quantitative levels of markers of systemic metabolic derangement following traumatic/haemorrhagic hypoxaemia, such as succinate, oxoproline, urate and fatty acids. These metabolites might contribute to coagulopathies of trauma and neutrophil priming driving acute lung injury. Future studies will investigate whether the observed compositional specificities mirror functional or pathological adaptations after trauma and haemorrhage.
The purpose of this descriptive study was to examine the associations of sleep hygiene and actigraphy measures of sleep with self-reported sleep quality in 197 pregnant women in northern Taiwan. Third-trimester pregnant women completed the Sleep Hygiene Practice Scale (SHPS) and the Pittsburgh Sleep Quality Index (PSQI) as well as the Center for Epidemiologic Studies-Depression Scale (CES-D), and wore an actigraph for 7 consecutive days. Student's t-test was used to compare the SHPS scores and means as well as variability of actigraphy sleep variables between poor sleepers (i.e., PSQI global score >5) and good sleepers (i.e., PSQI global score ≤5). Compared to good sleepers, poor sleepers reported significantly worse sleep hygiene, with higher SHPS scores and higher sleep schedule, arousal-related behavior, and sleep environment subscale scores. Poor sleepers had significantly greater intra-individual variability of sleep onset latency, total nighttime sleep, and wake after sleep onset than good sleepers. In stepwise linear regression, older maternal age (p = .01), fewer employment hours per week (p = .01), higher CES-D total score (p < .01), and higher SHPS arousal-related behavior subscale scores (p < .01) predicted self-reported global sleep quality. Findings support avoiding physically, physiologically, emotionally, or cognitively arousing activities before bedtime as a target for sleep-hygiene intervention in women during pregnancy. © 2015 Wiley Periodicals, Inc.
In recent years, previously unsuspected roles of astrocytes have been revealed, largely owing to the development of new tools enabling their selective study in situ. These exciting findings add to the large body of evidence demonstrating that astrocytes play a central role in brain homeostasis, in particular via the numerous cooperative metabolic processes they establish with neurons, such as the supply of energy metabolites and neurotransmitter recycling functions. Furthermore, impairments in astrocytic function are increasingly being recognized as an important contributor to neuronal dysfunction and, in particular, neurodegenerative processes. In this review, we discuss recent evidence supporting important roles for astrocytes in neuropathological conditions such as neuroinflammation, amyotrophic lateral sclerosis and Alzheimer's disease. We also explore the potential for neuroprotective therapeutics based on the modulation of astrocytic functions.
The transmembrane Na(+) concentration gradient is an important source of energy required not only to enable the generation of action potentials in excitable cells, but also for various transmembrane transporters both in excitable and non-excitable cells, like astrocytes. One of the vital functions of astrocytes in the central nervous system (CNS) is to regulate neurotransmitter concentrations in the extracellular space. Most neurotransmitters in the CNS are removed from the extracellular space by Na(+) -dependent neurotransmitter transporters (NeuTs) expressed both in neurons and astrocytes. Neuronal NeuTs control mainly phasic synaptic transmission, i.e., synaptically induced transient postsynaptic potentials, while astrocytic NeuTs contribute to the termination of phasic neurotransmission and modulate the tonic tone, i.e., the long-lasting activation of extrasynaptic receptors by neurotransmitter that has diffused out of the synaptic cleft. Consequently, local intracellular Na(+) ([Na(+) ]i ) transients occurring in astrocytes, for example via the activation of ionotropic neurotransmitter receptors, can affect the driving force for neurotransmitter uptake, in turn modulating the spatio-temporal profiles of neurotransmitter levels in the extracellular space. As some NeuTs are close to thermodynamic equilibrium under resting conditions, an increase in astrocytic [Na(+) ]i can stimulate the direct release of neurotransmitter via NeuT reversal. In this review we discuss the role of astrocytic [Na(+) ]i changes in the regulation of uptake/release of neurotransmitters. It is emphasized that an activation of one neurotransmitter system, including either its ionotropic receptor or Na(+) -coupled co-transporter, can strongly influence, or even reverse, other Na(+) -dependent NeuTs, with potentially significant consequences for neuronal communication. GLIA 2015.
Astrocytes exert multiple functions in the brain such as the development of blood-brain barrier characteristics, the promotion of neurovascular coupling, attraction of cells through the release of chemokines, clearance of toxic substances and generation of antioxidant molecules and growth factors. In this aspect, astrocytes secrete several growth factors (BDNF, GDNF, NGF, and others) that are fundamental for cell viability, oxidant protection, genetic expression and modulation of metabolic functions. The platelet derived growth factor (PDGF), which is expressed by many SNC cells including astrocytes, is an important molecule that has shown neuroprotective potential, improvement of wound healing, regulation of calcium metabolism and mitochondrial function. Here we explore some of these astrocyte-driven functions of growth factors and their possible therapeutic uses in the context of neurodegeneration.