The inhibitory neurotransmitter GABA evokes long‐lasting Ca2+ oscillations in cortical astrocytes

Studies over the last decade provided evidence that in a dynamic interaction with neurons glial cell astrocytes contribut to fundamental phenomena in the brain. Most of the knowledge on this derives, however, from studies monitoring the astrocyte Ca²⁺ response to glutamate. Whether astrocytes can similarly respond to other neurotransmitters, including the inhibitory neurotransmitter GABA, is relatively unexplored. By using confocal and two photon laser‐scanning microscopy the astrocyte response to GABA in the mouse somatosensory and temporal cortex was studied. In slices from developing (P15‐20) and adult (P30‐60) mice, it was found that in a subpopulation of astrocytes GABA evoked somatic Ca²⁺ oscillations. This response was mediated by GABA_B receptors and involved both G_i/o protein and inositol 1,4,5‐trisphosphate (IP₃) signalling pathways. In vivo experiments from young adult mice, revealed that also cortical astrocytes in the living brain exibit GABA_B receptor‐mediated Ca²⁺ elevations. At all astrocytic processes tested, local GABA or Baclofen brief applications induced long‐lasting Ca²⁺ oscillations, suggesting that all astrocytes have the potential to respond to GABA. Finally, in patch‐clamp recordings it was found that Ca²⁺ oscillations induced by Baclofen evoked astrocytic glutamate release and slow inward currents (SICs) in pyramidal cells from wild type but not IP₃R2^?/? mice, in which astrocytic GABA_B receptor‐mediated Ca²⁺ elevations are impaired. These data suggest that cortical astrocytes in the mouse brain can sense the activity of GABAergic interneurons and through their specific recruitment contribut to the distinct role played on the cortical network by the different subsets of GABAergic interneurons. GLIA 2016;64:363–373     

Possible neuroprotective property of nicotinic acetylcholine receptors in association with predominant upregulation of glial cell line-derived neurotrophic factor in astrocytes

The underlying mechanisms are still unclear for the neuroprotective properties of nicotine to date, whereas we have shown functional expression of nicotinic acetylcholine receptors (nAChRs) responsible for the influx of extracellular Ca²⁺ in cultured rat cortical astrocytes. In this study, we investigated the possible involvement of astrocytic nAChRs in the neuroprotection by this agonist. Exposure to nicotine predominantly induced mRNA expression of glial cell line‐derived neurotrophic factor (GDNF) among the different neurotrophic factors examined in cultured astrocytes, in a manner sensitive to nAChR antagonists, nifedipine, and aCa²⁺ chelator. Nicotine significantly increased GDNF in a concentration‐dependent manner in cultured astrocytes but not in neurons or neural progenitors even at the highest concentration used. In cultured astrocytes, a transient increase was seen in the expression of mRNA and corresponding protein for GDNF during sustained exposure to nicotine for 24 hr. Cytotoxicity mediated by oxidative, calcium, mitochondrial, or endoplasmic reticulum stress was invariably protected against in cortical neurons cultured with conditioned medium from astrocytes previously exposed to nicotine, and preincubation with the anti‐GDNF antibody reduced the neuroprotection by conditioned medium from astrocytes exposed to nicotine. Intraperitoneal administration of nicotine transiently increased the number of cells immunoreactive for both GDNF and glial fibrillary acidic protein in rat cerebral cortex. These results suggest that astrocytic nAChRs play a role in the neuroprotection against different cytotoxins after predominant upregulation of GDNF expression through a mechanism relevant to the acceleration of extracellular Ca²⁺ influx in rat brain in a particular situation. © 2012 Wiley Periodicals, Inc.     

Axons and astrocytes release ATP and glutamate to evoke calcium signals in NG2‐glia

NG2‐glia are an abundant population of cells in the adult CNS that make up a novel glial cell type. Here, we have examined calcium signals in NG2‐glia identified by expression of the fluorescent protein DsRed under the control of the NG2 promoter in the white matter of the mouse optic nerve. We focused on mice aged postnatal day (P)12–16, after the main period of oligodendrocyte generation. Using fluo‐4 and fura‐2 calcium imaging in isolated intact nerves, we show that glutamate and ATP evoke Ca²⁺ signals in NG2‐glia in situ, acting on AMPA‐type glutamate receptors and P2Y₁ and P2X₇ purine receptors; NMDA evoked a weak Ca²⁺ signal in a small proportion of NG2‐glia. We show that axonal action potentials and mechanical stimulation of astrocytes effect the release of glutamate and ATP to act on NG2‐glia; ATP alone evokes robust Ca²⁺ signals, whereas glutamate did not unless AMPA receptor desensitization was blocked with cyclothiazide. We identify the precise contacts that NG2‐glia form with axons at nodes of Ranvier, and the intricate bipartite sheaths formed between the processes of NG2‐glia and astrocytes. In addition, we provide evidence that NG2‐glia express synaptophysin, indicating they have mechanisms for transmitting as well as receiving signals. This study places NG2‐glia within a neuron‐glial network, and identifies roles for glutamate and ATP in communication with astrocytes as well as axons. © 2009 Wiley‐Liss, Inc.     

Glial ER and GAP junction mediated Ca2+ waves are crucial to maintain normal brain excitability

Astrocytes play key roles in regulating multiple aspects of neuronal function from invertebrates to humans and display Ca²⁺ fluctuations that are heterogeneously distributed throughout different cellular microdomains. Changes in Ca²⁺ dynamics represent a key mechanism for how astrocytes modulate neuronal activity. An unresolved issue is the origin and contribution of specific glial Ca²⁺ signaling components at distinct astrocytic domains to neuronal physiology and brain function. The Drosophila model system offers a simple nervous system that is highly amenable to cell-specific genetic manipulations to characterize the role of glial Ca²⁺ signaling. Here we identify a role for ER store-operated Ca²⁺ entry (SOCE) pathway in perineurial glia (PG), a glial population that contributes to the Drosophila blood–brain barrier. We show that PG cells display diverse Ca²⁺ activity that varies based on their locale within the brain. Ca²⁺ signaling in PG cells does not require extracellular Ca²⁺ and is blocked by inhibition of SOCE, Ryanodine receptors, or gap junctions. Disruption of these components triggers stimuli-induced seizure-like episodes. These findings indicate that Ca²⁺ release from internal stores and its propagation between neighboring glial cells via gap junctions are essential for maintaining normal nervous system function.     

Astrocyte glycogenolysis is triggered by store‐operated calcium entry and provides metabolic energy for cellular calcium homeostasis

Astrocytic glycogen, the only storage form of glucose in the brain, has been shown to play a fundamental role in supporting learning and memory, an effect achieved by providing metabolic support for neurons. We have examined the interplay between glycogenolysis and the bioenergetics of astrocytic Ca²⁺ homeostasis, by analyzing interdependency of glycogen and store‐operated Ca²⁺ entry (SOCE), a mechanism in cellular signaling that maintains high endoplasmatic reticulum (ER) Ca²⁺ concentration and thus provides the basis for store‐dependent Ca²⁺ signaling. We stimulated SOCE in primary cultures of murine cerebellar and cortical astrocytes, and determined glycogen content to investigate the effects of SOCE on glycogen metabolism. By blocking glycogenolysis, we tested energetic dependency of SOCE‐related Ca²⁺ dynamics on glycogenolytic ATP. Our results show that SOCE triggers astrocytic glycogenolysis. Upon inhibition of adenylate cyclase with 2',5'‐dideoxyadenosine, glycogen content was no longer significantly different from that in unstimulated control cells, indicating that SOCE triggers astrocytic glycogenolysis in a cAMP‐dependent manner. When glycogenolysis was inhibited in cortical astrocytes by 1,4‐dideoxy‐1,4‐imino‐D‐arabinitol, the amount of Ca²⁺ loaded into ER via sarco/endoplasmic reticulum Ca²‐ATPase (SERCA) was reduced, which suggests that SERCA pumps preferentially metabolize glycogenolytic ATP. Our study demonstrates SOCE as a novel pathway in stimulating astrocytic glycogenolysis. We also provide first evidence for a new functional role of brain glycogen, in providing local ATP to SERCA, thus establishing the bioenergetic basis for astrocytic Ca²⁺ signaling. This mechanism could offer a novel explanation for the impact of glycogen on learning and memory. GLIA 2014;62:526–534     

GFAP-positive hippocampal astrocytes in situ respond to glutamatergic neuroligands with increases in [Ca2+]i

It is becoming increasingly clear that astrocytes play very dynamic and interactive roles that are important for the normal functioning of the central nervous system. In culture, astrocytes express many receptors coupled to increases in intracellular calcium ([Ca²⁺]_i). In vivo, it is likely that these receptors are important for the modulation of astrocytic functions such as the uptake of neurotransmitters and ions. Currently, however, very little is known about the expression or stimulation of such astrocytic receptors in vivo. To address this issue, confocal microscopy and calcium sensitive fluorescent dyes were used to examine the dynamic changes in astrocytic [Ca²⁺]_i, within acutely isolated hippocampal slices. Astrocytes were subsequently identified by immunocytochemistry for glial fibrillary acidic protein. In this paper, we present data indicating that hippocampal astrocytes in situ respond to glutamate, kainate, α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), 1-aminocyclopentane-trans-1,3-dicarboxylic acid (t-ACPD), N-methyl-D-aspartate (NMDA), and depolarization with increases in [Ca²⁺]_i. The increases in [Ca²⁺]_i occurred in both the astrocytic cell bodies and the processes. Temporally the changes in [Ca²⁺]_i were very dynamic, and various patterns ranging from sustained elevations to oscillations of [Ca²⁺]_i were observed. Individual astrocytes responded to neuroligands selective for both ionotropic and metabotropic glutamate receptors with increases in [Ca²⁺]_i. These findings indicate that astrocytes in vivo contain glutamatergic receptors coupled to increases in [C²⁺]_i and are able to respond to neuronally released neurotransmitters. (c) 1995 Wiley-Liss, Inc.     

Glial Na+‐dependent ion transporters in pathophysiological conditions

Sodium dynamics are essential for regulating functional processes in glial cells. Indeed, glial Na⁺ signaling influences and regulates important glial activities, and plays a role in neuron‐glia interaction under physiological conditions or in response to injury of the central nervous system (CNS). Emerging studies indicate that Na⁺ pumps and Na⁺‐dependent ion transporters in astrocytes, microglia, and oligodendrocytes regulate Na⁺ homeostasis and play a fundamental role in modulating glial activities in neurological diseases. In this review, we first briefly introduced the emerging roles of each glial cell type in the pathophysiology of cerebral ischemia, Alzheimer's disease, epilepsy, Parkinson's disease, Amyotrophic Lateral Sclerosis, and myelin diseases. Then, we discussed the current knowledge on the main roles played by the different glial Na⁺‐dependent ion transporters, including Na⁺/K⁺ ATPase, Na⁺/Ca²⁺ exchangers, Na⁺/H⁺ exchangers, Na⁺‐K⁺‐Cl^? cotransporters, and Na⁺‐ cotransporter in the pathophysiology of the diverse CNS diseases. We highlighted their contributions in cell survival, synaptic pathology, gliotransmission, pH homeostasis, and their role in glial activation, migration, gliosis, inflammation, and tissue repair processes. Therefore, this review summarizes the foundation work for targeting Na⁺‐dependent ion transporters in glia as a novel strategy to control important glial activities associated with Na⁺ dynamics in different neurological disorders. GLIA 2016;64:1677–1697     

Spatial organization of NG2 glial cells and astrocytes in rat hippocampal CA1 region

Similar to astrocytes, NG2 glial cells are uniformly distributed in the central nervous system (CNS). However, little is known about the interspatial relationship, nor the functional interactions between these two star‐shaped glial subtypes. Confocal morphometric analysis showed that NG2 immunostained cells are spatially organized as domains in rat hippocampal CA1 region and that each NG2 glial domain occupies a spatial volume of ～178, 364 μm³. The processes of NG2 glia and astrocytes overlap extensively; each NG2 glial domain interlaces with the processes deriving from 5.8 ± 0.4 neighboring astrocytes, while each astrocytic domain accommodates processes stemming from 4.5 ± 0.3 abutting NG2 glia. In CA1 stratum radiatum, the cell bodies of morphologically identified glial cells often appear to make direct somatic‐somata contact, termed as doublets. We used dual patch recording and postrecording NG2/GFAP double staining to determine the glial identities of these doublets. We show that among 44 doublets, 50% were NG2 glia–astrocyte pairs, while another 38.6% and 11.4% were astrocyte–astrocyte and NG2 glia–NG2 glia pairs, respectively. In dual patch recording, neither electrical coupling nor intercellular biocytin transfer was detected in astrocyte–NG2 glia or NG2 glia–NG2 glia doublets. Altogether, although NG2 glia and astrocytes are not gap junction coupled, their cell bodies and processes are interwoven extensively. The anatomical and physiological relationships revealed in this study should facilitate future studies to understand the metabolic coupling and functional communication between NG2 glia and astrocytes. © 2013 Wiley Periodicals, Inc.     

Neurotransmitters involved in fast excitatory neurotransmission directly activate enteric glial cells

Background The intimate association between glial cells and neurons within the enteric nervous system has confounded careful examination of the direct responsiveness of enteric glia to different neuroligands. Therefore, we aimed to investigate whether neurotransmitters known to elicit fast excitatory potentials in enteric nerves also activate enteric glia directly. Methods We studied the effect of acetylcholine (ACh), serotonin (5‐HT), and adenosine triphosphate (ATP) on intracellular Ca²⁺ signaling using aequorin‐expressing and Fluo‐4 AM‐loaded CRL‐2690 rat and human enteric glial cell cultures devoid of neurons. The influence of these neurotransmitters on the proliferation of glia was measured and their effect on the expression of c‐Fos as well as glial fibrillary acidic protein (GFAP), Sox10, and S100 was examined by immunohistochemistry and quantitative RT‐PCR. Key Results Apart from ATP, also ACh and 5‐HT induced a dose‐dependent increase in intracellular Ca²⁺ concentration in CRL‐2690 cells. Similarly, these neurotransmitters also evoked Ca²⁺ transients in human primary enteric glial cells obtained from mucosal biopsies. In contrast with ATP, stimulation with ACh and 5‐HT induced early gene expression in CRL‐2690 cells. The proliferation of enteric glia and their expression of GFAP, Sox10, and S100 were not affected following stimulation with these neurotransmitters. Conclusions & Inferences We provide evidence that enteric glial cells respond to fast excitatory neurotransmitters by changes in intracellular Ca²⁺. On the basis of our experimental in vitro setting, we show that enteric glia are not only directly responsive to purinergic but also to serotonergic and cholinergic signaling mechanisms.     

Calcitonin gene‐related peptide (CGRP) triggers Ca2+ responses in cultured astrocytes and in Bergmann glial cells from cerebellar slices

The neuropeptide calcitonin gene‐related peptide (CGRP) is transiently expressed in cerebellar climbing fibers during development while its receptor is mainly expressed in astrocytes, in particular Bergmann glial cells. Here, we analyzed the effects of CGRP on astrocytic calcium signaling. Mouse cultured astrocytes from cerebellar or cerebral cortex as well as Bergmann glial cells from acutely isolated cerebellar slices were loaded with the Ca²⁺ sensor Fura‐2. CGRP triggered transient increases in intracellular Ca²⁺ in astrocytes in culture as well as in acute slices. Responses were observed in the concentration range of 1 nm to 1 mm , in both the cell body and its processes. The calcium transients were dependent on release from intracellular stores as they were blocked by thapsigargin but not by the absence of extracellular calcium. In addition, after CGRP application a further delayed transient increase in calcium activity could be observed. Finally, cerebellar astrocytes from neonatal mice expressed receptor component protein, a component of the CGRP receptor, as revealed by immunofluorescence and confocal microscopy. It is thus proposed that the CGRP‐containing afferent fibers in the cerebellum (the climbing fibers) modulate calcium in astrocytes by releasing the neuropeptide during development and hence possibly influence the differentiation of Purkinje cells.     

Functional rhythmogenic domains defined by astrocytic networks in the trigeminal main sensory nucleus

Stimuli that induce rhythmic firing in trigeminal neurons also increase astrocytic coupling and reveal networks that define the boundaries of this particular population. Rhythmic firing depends on astrocytic coupling which in turn depends on S100β. In many nervous functions that rely on the ability of neuronal networks to generate a rhythmic pattern of activity, coordination of firing is an essential feature. Astrocytes play an important role in some of these networks, but the contribution of astrocytic coupling remains poorly defined. Here we investigate the modulation and organization of astrocytic networks in the dorsal part of the trigeminal main sensory nucleus (NVsnpr), which forms part of the network generating chewing movements. Using whole‐cell recordings and the dye coupling approach by filling a single astrocyte with biocytin to reveal astrocytic networks, we showed that coupling is limited under resting conditions, but increases importantly under conditions that induce rhythmic firing in NVsnpr neurons. These are: repetitive electrical stimulation of the sensory inputs to the nucleus, local application of NMDA and decrease of extracellular Ca²⁺. We have previously shown that rhythmic firing induced in NVsnpr neurons by these stimuli depends on astrocytes and their Ca²⁺‐binding protein S100β. Here we show that extracellular blockade of S100β also prevents the increase in astrocytic coupling induced by local application of NMDA. Most of the networks were small and remained confined to the functionally distinct area of dorsal NVsnpr. Disrupting coupling by perfusion with the nonspecific gap junction blocker, carbenoxolone or with GAP26, a selective inhibitor of connexin 43, mostly expressed in astrocytes, abolished NMDA‐induced rhythmic firing in NVsnpr neurons. These results suggest that astrocytic coupling is regulated by sensory inputs, necessary for neuronal bursting, and organized in a region specific manner.     

Inositol 1,4,5-trisphosphate receptor type 2-independent Ca2+ release from the endoplasmic reticulum in astrocytes

Accumulating evidence indicates that astrocytes are actively involved in the physiological and pathophysiological functions of the brain. Intracellular Ca²⁺ signaling, especially Ca²⁺ release from the endoplasmic reticulum (ER), is considered to be crucial for the regulation of astrocytic functions. Mice with genetic deletion of inositol 1,4,5-trisphosphate receptor type 2 (IP₃R2) are reportedly devoid of astrocytic Ca²⁺ signaling, and thus widely used to explore the roles of Ca²⁺ signaling in astrocytic functions. While functional deficits in IP₃R2-knockout (KO) mice have been found in some reports, no functional deficit was observed in others. Thus, there remains a controversy regarding the functional significance of astrocytic Ca²⁺ signaling. To address this controversy, we re-evaluated the assumption that Ca²⁺ release from the ER is abolished in IP₃R2-KO astrocytes using a highly sensitive imaging technique. We expressed the ER luminal Ca²⁺ indicator G-CEPIA1er in cortical and hippocampal astrocytes to directly visualize spontaneous and stimulus-induced Ca²⁺ release from the ER. We found attenuated but significant Ca²⁺ release in response to application of norepinephrine to IP₃R2-KO astrocytes. This IP₃R2-independent Ca²⁺ release induced only minimal cytosolic Ca²⁺ transients but induced robust Ca²⁺ increases in mitochondria that are frequently in close contact with the ER. These results indicate that ER Ca²⁺ release is retained and is sufficient to increase the Ca²⁺ concentration in close proximity to the ER in IP₃R2-KO astrocytes.     

Astrocytes: integrators of arousal state and sensory context

The integration of external information with the internal state of the body is central to the survival of virtually every multicellular organism. However, a complete picture of the mechanisms that govern this process is lacking. In this opinion article, we synthesize evidence demonstrating that astrocytes sense the momentary arousal state – through neuromodulator release – as well as the sensory inputs – through local synaptic activity – and respond to them with changes in calcium (Ca²⁺) signaling. We hypothesize that astrocytes integrate sensory signals with the internal state and that this process is necessary to secure optimal behavior. Finally, we argue that dysfunctional astrocytic Ca²⁺ signaling could be an underlying factor in disorders characterized by disrupted sensory processing.     

Astrocyte‐mediated synapse remodeling in the pathological brain

Astrocytes, a major type of glia, reciprocally influence synaptic transmission and connectivity, forming the “tripartite synapses”. Astrocytic metabotropic glutamate receptor (mGluR)‐mediated Ca²⁺ waves and release of gliotransmitters or synaptogenic molecules mediate this neuron‐glia interaction in the developing brain, but this signaling has been challenged for adult brain. However, cumulative evidence has suggested that mature astrocytes exhibit re‐awakening of such immature phenotype in the pathological adult brain. This phenotypic change in astrocytes in response to injury may induce neural circuit and synapse plasticity. In this review article, we summarize astrocyte‐mediated synapse remodeling during physiological development, discuss re‐emergence of immature astrocytic signaling in adult pathological brain, and finally highlight its contribution to significant modification of synaptic connections correlating with functional progress of brain pathology.     

Cholesterol regulates polymodal sensory transduction in Müller glia

Over‐ and underexposure to cholesterol activates glia in neurodegenerative brain and retinal diseases but the molecular targets of cholesterol in glial cells are not known. Here, we report that disruption of unesterified membrane cholesterol content modulates the transduction of chemical, mechanical and temperature stimuli in mouse Müller cells. Activation of TRPV4 (transient receptor potential vanilloid type 4), a nonselective polymodal cation channel was studied following the removal or supplementation of cholesterol using the methyl‐beta cyclodextrin (MβCD) delivery vehicle. Cholesterol extraction disrupted lipid rafts and caveolae without affecting TRPV4 trafficking or membrane localization protein. However, MβCD suppressed agonist (GSK1016790A)‐ and temperature‐evoked elevations in [Ca²⁺]_i, and suppressed transcellular propagation of Ca²⁺ waves. Lowering the free membrane cholesterol content markedly prolonged the time‐course of the glial swelling response, whereas MβCD:cholesterol supplementation enhanced agonist‐ and temperature‐induced Ca²⁺ signals and shortened the swelling response. Taken together, these data show that membrane cholesterol modulates polymodal transduction of agonists, swelling and temperature stimuli in retinal radial glia and suggest that dyslipidemic retinas might be associated with abnormal glial transduction of ambient sensory inputs.     

Plasmalemmal and mitochondrial Na+‐Ca2+ exchange in neuroglia

In the absence of the electrical signaling for which neurons are so highly specialized, GLIA rely on the slow propagation of ionic signals to mediate network events such as Ca²⁺ and Na⁺ waves. Glia differ from neurons in another important way, they are replete with a high density of ionic‐transport proteins that are essential for them to fulfil their basic functions as guardians of the intra and extra‐cellular milieux. Both the signaling and the homeostatic properties of glial cells are therefore particularly dependent upon the regulation of the two principle physiological metal cations, Ca²⁺ and Na⁺. For both ions, glia express high‐affinity/low capacity ATP‐fuelled pumps that can rapidly move small numbers of ions against an electro‐chemical gradient. For both Ca²⁺ and Na⁺ regulation, a single transporter family, the Na⁺‐Ca²⁺ exchanger (NCX), is used to maintain cellular ion homeostasis over the longer term and under conditions of prolonged or acute ionic dysregulation in astrocytes, oligodendroglia and microglia. Our understanding of glial NCX, both plasmalemmal and mitochondrial, is undergoing the kind of transformation that our understanding of glial cells, in general, has undergone in recent decades. These exchange proteins are becoming increasingly recognized for their essential roles in intracellular homeostasis while their signaling functions are starting to come to light. This review summarizes these key aspects and highlights the many areas where work has yet to begin in this rapidly evolving field. GLIA 2016;64:1646–1654     

Astrocyte‐restricted disruption of connexin‐43 impairs neuronal plasticity in mouse barrel cortex

There is intensive gap‐junctional coupling between glial processes, but their significance in sensory functions remains unknown. Connexin‐43 (Cx43), a major component of astrocytic gap‐junction channels, is abundantly expressed in astrocytes. To investigate the role of Cx43‐mediated gap junctions between astrocytes in sensory functions, we generated Cx43 knockout (KO) mice with a mouse line carrying loxP sites flanking exon 2 of the Cx43 gene and the transgenic line expressing Cre recombinase under control of the glial fibrillary acidic protein promoter, which exhibited a significant loss of Cx43 in astrocytes in the barrel cortex. Although Cx43 expression between the astrocytes measured by immunohistochemistry was virtually abolished in Cx43 KO mice, they had normal architecture in the barrel cortex but the intensity of cytochrome oxide histochemistry decreased significantly. In vivo electrophysiological analysis revealed that the long‐term potentiation of the vibrissal evoked responses in the barrel cortex evoked by high‐frequency rhythmic vibrissal stimuli (100 Hz, 1 s) was abolished in Cx43 KO mice. Current source density analysis also revealed that astrocytic Cx43 was important to the flow of excitation within the laminar connections in barrel cortex. Behavioral tests showed that the ability of Cx43 KO mice to sense the environment with their whiskers decreased. Even so, the jump‐stand experiment showed that they could still discriminate rough from smooth surfaces. Our findings suggest that Cx43‐mediated gap‐junctional coupling between astrocytes is important in the neuron–glia interactions required for whisker‐related sensory functions and plasticity.     

Astrocyte dysfunction in Alzheimer disease

Astrocytes are glial cells that are distributed throughout the central nervous system in an arrangement optimal for chemical and physical interaction with neuronal synapses and brain blood supply vessels. Neurotransmission modulates astrocytic excitability by activating an array of cell surface receptors and transporter proteins, resulting in dynamic changes in intracellular Ca²⁺ or Na⁺. Ionic and electrogenic astrocytic changes, in turn, drive vital cell nonautonomous effects supporting brain function, including regulation of synaptic activity, neuronal metabolism, and regional blood supply. Alzheimer disease (AD) is associated with aberrant oligomeric amyloid β generation, which leads to extensive proliferation of astrocytes with a reactive phenotype and abnormal regulation of these processes. Astrocytic morphology, Ca²⁺ responses, extracellular K⁺ removal, glutamate transport, amyloid clearance, and energy metabolism are all affected in AD, resulting in a deleterious set of effects that includes glutamate excitotoxicity, impaired synaptic plasticity, reduced carbon delivery to neurons for oxidative phosphorylation, and dysregulated linkages between neuronal energy demand and regional blood supply. This review summarizes how astrocytes are affected in AD and describes how these changes are likely to influence brain function. © 2017 Wiley Periodicals, Inc.