Astrocytes and Behavior.

Animal behavior was classically considered to be determined exclusively by neuronal activity, whereas surrounding glial cells such as astrocytes played only supportive roles. However, astrocytes are as numerous as neurons in the mammalian brain, and current findings indicate a chemically based dialog between astrocytes and neurons. Activation of astrocytes by synaptically released neurotransmitters converges on regulating intracellular Ca2+ in astrocytes, which then can regulate the efficacy of near and distant tripartite synapses at diverse timescales through gliotransmitter release. Here, we discuss recent evidence on how diverse behaviors are impacted by this dialog. These recent findings support a paradigm shift in neuroscience, in which animal behavior does not result exclusively from neuronal activity but from the coordinated activity of both astrocytes and neurons. Decoding how astrocytes and neurons interact with each other in various brain circuits will be fundamental to fully understanding how behaviors originate and become dysregulated in disease.

Glial Connexins and Pannexins in the Healthy and Diseased Brain.

Over the past several decades a large amount of data have established that glial cells, the main cell population in the brain, dynamically interact with neurons and thus impact their activity and survival. One typical feature of glia is their marked expression of several connexins, the membrane proteins forming intercellular gap junction channels and hemichannels. Pannexins, which have a tetraspan membrane topology as connexins, are also detected in glial cells. Here, we review the evidence that connexin and pannexin channels are actively involved in dynamic and metabolic neuroglial interactions in physiological as well as in pathological situations. These features of neuroglial interactions open the way to identify novel non-neuronal aspects that allow for a better understanding of behavior and information processing performed by neurons. This will also complement the "neurocentric" view by facilitating the development of glia-targeted therapeutic strategies in brain disease.

Multiple forms of working memory emerge from synapse-astrocyte interactions in a neuron-glia network model.

Persistent activity in populations of neurons, time-varying activity across a neural population, or activity-silent mechanisms carried out by hidden internal states of the neural population have been proposed as different mechanisms of working memory (WM). Whether these mechanisms could be mutually exclusive or occur in the same neuronal circuit remains, however, elusive, and so do their biophysical underpinnings. While WM is traditionally regarded to depend purely on neuronal mechanisms, cortical networks also include astrocytes that can modulate neural activity. We propose and investigate a network model that includes both neurons and glia and show that glia-synapse interactions can lead to multiple stable states of synaptic transmission. Depending on parameters, these interactions can lead in turn to distinct patterns of network activity that can serve as substrates for WM.

Autoimmune inflammation triggers aberrant astrocytic calcium signaling to impair synaptic plasticity.

Cortical pathology involving inflammatory and neurodegenerative mechanisms is a hallmark of multiple sclerosis and a correlate of disease progression and cognitive decline. Astrocytes play a pivotal role in multiple sclerosis initiation and progression but astrocyte-neuronal network alterations contributing to gray matter pathology remain undefined. Here we unveil deregulation of astrocytic calcium signaling and astrocyte-to-neuron communication as key pathophysiological mechanisms of cortical dysfunction in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis. Using two-photon imaging ex vivo and fiber photometry in freely behaving mice, we found that acute EAE was associated with the emergence of spontaneously hyperactive cortical astrocytes exhibiting dysfunctional responses to cannabinoid, glutamate and purinoreceptor agonists. Abnormal astrocyte signaling by Gi and Gq protein coupled receptors was observed in the inflamed cortex. This was mirrored by treatments with pro-inflammatory factors both in vitro and ex vivo, suggesting cell-autonomous effects of the cortical neuroinflammatory environment. Finally, deregulated astrocyte calcium activity was associated with an enhancement of glutamatergic gliotransmission and a shift of astrocyte-mediated short-term and long-term plasticity mechanisms towards synaptic potentiation. Overall, our data identify astrocyte-neuronal network dysfunctions as key pathological features of gray matter inflammation in multiple sclerosis and potentially additional neuroimmunological disorders.

Endocannabinoid signaling in astrocytes.

The study of the astrocytic contribution to brain functions has been growing in popularity in the neuroscience field. In the last years, and especially since the demonstration of the involvement of astrocytes in synaptic functions, the astrocyte field has revealed multiple functions of these cells that seemed inconceivable not long ago. In parallel, cannabinoid investigation has also identified different ways by which cannabinoids are able to interact with these cells, modify their functions, alter their communication with neurons and impact behavior. In this review, we will describe the expression of different endocannabinoid system members in astrocytes. Moreover, we will relate the latest findings regarding cannabinoid modulation of some of the most relevant astroglial functions, namely calcium (Ca2+ ) dynamics, gliotransmission, metabolism, and inflammation.

Spontaneous and multifaceted ATP release from astrocytes at the scale of hundreds of synapses.

Astrocytes participate in information processing by releasing neuroactive substances termed gliotransmitters, including ATP. Individual astrocytes come into contact with thousands of synapses with their ramified structure, but the spatiotemporal dynamics of ATP gliotransmission remains unclear, especially in physiological brain tissue. Using a genetically encoded fluorescent sensor, GRABATP1.0 , we discovered that extracellular ATP increased locally and transiently in absence of stimuli in neuron-glia co-cultures, cortical slices, and the anesthetized mouse brain. Spontaneous ATP release events were tetrodotoxin-insensitive but suppressed by gliotoxin, fluorocitrate, and typically spread over 50-250 µm2 area at concentrations capable of activating purinergic receptors. Besides, most ATP events did not coincide with Ca2+ transients, and intracellular Ca2+ buffering with BAPTA-AM did not affect ATP event frequency. Clustering analysis revealed that these events followed multiple distinct kinetics, and blockade of exocytosis only decreased a minor group of slow events. Overall, astrocytes spontaneously release ATP through multiple mechanisms, mainly in non-vesicular and Ca2+ -independent manners, thus potentially regulating hundreds of synapses all together.

Altered calcium signaling in Bergmann glia contributes to spinocerebellar ataxia type-1 in a mouse model of SCA1.

Spinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disease caused by an abnormal expansion of glutamine (Q) encoding CAG repeats in the ATAXIN1 (ATXN1) gene and characterized by progressive cerebellar ataxia, dysarthria, and eventual deterioration of bulbar functions. SCA1 shows severe degeneration of cerebellar Purkinje cells (PCs) and activation of Bergmann glia (BG), a type of cerebellar astroglia closely associated with PCs. Combining electrophysiological recordings, calcium imaging techniques, and chemogenetic approaches, we have investigated the electrical intrinsic and synaptic properties of PCs and the physiological properties of BG in SCA1 mouse model expressing mutant ATXN1 only in PCs. PCs of SCA1 mice displayed lower spontaneous firing rate and larger slow afterhyperpolarization currents (sIAHP) than wildtype mice, whereas the properties of the synaptic inputs were unaffected. BG of SCA1 mice showed higher calcium hyperactivity and gliotransmission, manifested by higher frequency of NMDAR-mediated slow inward currents (SICs) in PC. Preventing the BG calcium hyperexcitability of SCA1 mice by loading BG with the calcium chelator BAPTA restored sIAHP and spontaneous firing rate of PCs to similar levels of wildtype mice. Moreover, mimicking the BG hyperactivity by activating BG expressing Gq-DREADDs in wildtype mice reproduced the SCA1 pathological phenotype of PCs, i.e., enhancement of sIAHP and decrease of spontaneous firing rate. These results indicate that the intrinsic electrical properties of PCs, but not their synaptic properties, were altered in SCA1 mice and that these alterations were associated with the hyperexcitability of BG. Moreover, preventing BG hyperexcitability in SCA1 mice and promoting BG hyperexcitability in wildtype mice prevented and mimicked, respectively, the pathological electrophysiological phenotype of PCs. Therefore, BG plays a relevant role in the dysfunction of the electrical intrinsic properties of PCs in SCA1 mice, suggesting that they may serve as potential targets for therapeutic approaches to treat the spinocerebellar ataxia type 1.

Dysregulation of astrocytic Ca2+ signaling and gliotransmitter release in mouse models of α-synucleinopathies.

α-Synuclein is a major component of Lewy bodies (LB) and Lewy neurites (LN) appearing in the postmortem brain of Parkinson's disease (PD) and other α-synucleinopathies. While most studies of α-synucleinopathies have focused on neuronal and synaptic alterations as well as dysfunctions of the astrocytic homeostatic roles, whether the bidirectional astrocyte-neuronal communication is affected in these diseases remains unknown. We have investigated whether the astrocyte Ca2+ excitability and the glutamatergic gliotransmission underlying astrocyte-neuronal signaling are altered in several transgenic mouse models related to α-synucleinopathies, i.e., mice expressing high and low levels of the human A53T mutant α-synuclein (G2-3 and H5 mice, respectively) globally or selectively in neurons (iSyn mice), mice expressing human wildtype α-synuclein (I2-2 mice), and mice expressing A30P mutant α-synuclein (O2 mice). Combining astrocytic Ca2+ imaging and neuronal electrophysiological recordings in hippocampal slices of these mice, we have found that compared to non-transgenic mice, astrocytes in G2-3 mice at different ages (1-6 months) displayed a Ca2+ hyperexcitability that was independent of neurotransmitter receptor activation, suggesting that the expression of α-synuclein mutant A53T altered the intrinsic properties of astrocytes. Similar dysregulation of the astrocyte Ca2+ signal was present in H5 mice, but not in I2-2 and O2 mice, indicating α-synuclein mutant-specific effects. Moreover, astrocyte Ca2+ hyperexcitability was absent in mice expressing the α-synuclein mutant A53T selectively in neurons, indicating that the effects on astrocytes were cell-autonomous. Consistent with these effects, glutamatergic gliotransmission was enhanced in G2-3 and H5 mice, but was unaffected in I2-2, O2 and iSyn mice. These results indicate a cell-autonomous effect of pathogenic A53T expression in astrocytes that may contribute to the altered neuronal and synaptic function observed in α-synucleinopathies.

Enhanced Astrocyte Activity and Excitatory Synaptic Function in the Hippocampus of Pentylenetetrazole Kindling Model of Epilepsy.

Epilepsy is a chronic condition characterized by recurrent spontaneous seizures. The interaction between astrocytes and neurons has been suggested to play a role in the abnormal neuronal activity observed in epilepsy. However, the exact way astrocytes influence neuronal activity in the epileptogenic brain remains unclear. Here, using the PTZ-induced kindling mouse model, we evaluated the interaction between astrocyte and synaptic function by measuring astrocytic Ca2+ activity, neuronal excitability, and the excitatory/inhibitory balance in the hippocampus. Compared to control mice, hippocampal slices from PTZ-kindled mice displayed an increase in glial fibrillary acidic protein (GFAP) levels and an abnormal pattern of intracellular Ca2+-oscillations, characterized by an increased frequency of prolonged spontaneous transients. PTZ-kindled hippocampal slices also showed an increase in the E/I ratio towards excitation, likely resulting from an augmented release probability of excitatory inputs without affecting inhibitory synapses. Notably, the alterations in the release probability seen in PTZ-kindled slices can be recovered by reducing astrocyte hyperactivity with the reversible toxin fluorocitrate. This suggests that astroglial hyper-reactivity enhances excitatory synaptic transmission, thereby impacting the E/I balance in the hippocampus. Altogether, our findings support the notion that abnormal astrocyte-neuron interactions are pivotal mechanisms in epileptogenesis.

Assessment of astrocytes as a mediator of memory and learning in rodents.

The classical view of astrocytes is that they provide supportive functions for neurons, transporting metabolites and maintaining the homeostasis of the extracellular milieu. This view is gradually changing with the advent of molecular genetics and optical methods allowing interrogation of selected cell types in live experimental animals. An emerging view that astrocytes additionally act as a mediator of synaptic plasticity and contribute to learning processes has gained in vitro and in vivo experimental support. Here we focus on the literature published in the past two decades to review the roles of astrocytes in brain plasticity in rodents, whereby the roles of neurotransmitters and neuromodulators are considered to be comparable to those in humans. We outline established inputs and outputs of astrocytes and discuss how manipulations of astrocytes have impacted the behavior in various learning paradigms. Multiple studies suggest that the contribution of astrocytes has a considerably longer time course than neuronal activation, indicating metabolic roles of astrocytes. We advocate that exploring upstream and downstream mechanisms of astrocytic activation will further provide insight into brain plasticity and memory/learning impairment.

Astrocyte control of the entorhinal cortex-dentate gyrus circuit: Relevance to cognitive processing and impairment in pathology.

The entorhinal cortex-dentate gyrus circuit is centrally involved in memory processing conveying to the hippocampus spatial and nonspatial context information via, respectively, medial and lateral perforant path (MPP and LPP) excitatory projections onto dentate granule cells (GCs). Here, we review work of several years from our group showing that astrocytes sense local synaptic transmission and exert in turn a presynaptic control at PP-GC synapses. Modulation of neurotransmitter release probability by astrocytes sets basal synaptic strength and dynamic range for long-term potentiation of PP-GC synapses. Intriguingly, this astrocyte control is circuit-specific, being present only at MPP-GC (not LPP-GC) synapses, which selectively express atypical presynaptic N-methyl-D-aspartate receptors (NMDAR) suitable to activation by astrocyte-released glutamate. Moreover, the astrocytic control is peculiarly dependent on the cytokine TNFα, which at constitutive levels acts as a gating factor for the astrocyte signaling. During inflammation/infection processes, increased levels of TNFα lead to uncontrolled astrocyte glutamate release, altered PP-GC circuit processing and, ultimately, impaired contextual memory performance. The TNFα-dependent pathological switch of the synaptic control from astrocytes and its deleterious consequences are observed in animal models of HIV brain infection and multiple sclerosis, conditions both known to cause cognitive disturbances in up to 50% of patients. The review also discusses open issues related to the identified astrocytic pathway: its role in contextual memory processing, potential damaging role in Alzheimer's disease, the existence of vesicular glutamate release from DG astrocytes, and the possible synaptic-like connectivity between astrocytic output sites and PP receptive sites.

Improved gliotransmission by increasing intracellular Ca2+ via TRPV1 on multi-walled carbon nanotube platforms.

BACKGROUND: Astrocyte is a key regulator of neuronal activity and excitatory/inhibitory balance via gliotransmission. Recently, gliotransmission has been identified as a novel target for neurological diseases. However, using the properties of nanomaterials to modulate gliotransmission has not been uncovered. RESULTS: We prepared non-invasive CNT platforms for cells with different nanotopography and properties such as hydrophilicity and conductivity. Using CNT platforms, we investigated the effect of CNT on astrocyte functions participating in synaptic transmission by releasing gliotransmitters. Astrocytes on CNT platforms showed improved cell adhesion and proliferation with upregulated integrin and GFAP expression. In addition, intracellular GABA and glutamate in astrocytes were augmented on CNT platforms. We also demonstrated that gliotransmitters in brain slices were increased by ex vivo incubation with CNT. Additionally, intracellular resting Ca2+ level, which is important for gliotransmission, was also increased via TRPV1 on CNT platforms. CONCLUSION: CNT can improve astrocyte function including adhesion, proliferation and gliotransmission by increasing resting Ca2+ level. Therefore, our study suggests that CNT would be utilized as a new therapeutic platform for central nervous system diseases by modulating gliotransmission.

The NMDA receptor activation by d-serine and glycine is controlled by an astrocytic Phgdh-dependent serine shuttle.

Astrocytes express the 3-phosphoglycerate dehydrogenase (Phgdh) enzyme required for the synthesis of l-serine from glucose. Astrocytic l-serine was proposed to regulate NMDAR activity by shuttling to neurons to sustain d-serine production, but this hypothesis remains untested. We now report that inhibition of astrocytic Phgdh suppressed the de novo synthesis of l-and d-serine and reduced the NMDAR synaptic potentials and long-term potentiation (LTP) at the Schaffer collaterals-CA1 synapse. Likewise, enzymatic removal of extracellular l-serine impaired LTP, supporting an l-serine shuttle mechanism between glia and neurons in generating the NMDAR coagonist d-serine. Moreover, deletion of serine racemase (SR) in glutamatergic neurons abrogated d-serine synthesis to the same extent as Phgdh inhibition, suggesting that neurons are the predominant source of the newly synthesized d-serine. We also found that the synaptic NMDAR activation in adult SR-knockout (KO) mice requires Phgdh-derived glycine, despite the sharp decline in the postnatal glycine levels as a result of the emergence of the glycine cleavage system. Unexpectedly, we also discovered that glycine regulates d-serine metabolism by a dual mechanism. The first consists of tonic inhibition of SR by intracellular glycine observed in vitro, primary cultures, and in vivo microdialysis. The second involves a transient glycine-induce d-serine release through the Asc-1 transporter, an effect abolished in Asc-1 KO mice and diminished by deleting SR in glutamatergic neurons. Our observations suggest that glycine is a multifaceted regulator of d-serine metabolism and implicate both d-serine and glycine in mediating NMDAR synaptic activation at the mature hippocampus through a Phgdh-dependent shuttle mechanism.

GABAergic Regulation of Astroglial Gliotransmission through Cx43 Hemichannels.

Gamma-Aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the brain. It is produced by interneurons and recycled by astrocytes. In neurons, GABA activates the influx of Cl- via the GABAA receptor or efflux or K+ via the GABAB receptor, inducing hyperpolarization and synaptic inhibition. In astrocytes, the activation of both GABAA and GABAB receptors induces an increase in intracellular Ca2+ and the release of glutamate and ATP. Connexin 43 (Cx43) hemichannels are among the main Ca2+-dependent cellular mechanisms for the astroglial release of glutamate and ATP. However, no study has evaluated the effect of GABA on astroglial Cx43 hemichannel activity and Cx43 hemichannel-mediated gliotransmission. Here we assessed the effects of GABA on Cx43 hemichannel activity in DI NCT1 rat astrocytes and hippocampal brain slices. We found that GABA induces a Ca2+-dependent increase in Cx43 hemichannel activity in astrocytes mediated by the GABAA receptor, as it was blunted by the GABAA receptor antagonist bicuculline but unaffected by GABAB receptor antagonist CGP55845. Moreover, GABA induced the Cx43 hemichannel-dependent release of glutamate and ATP, which was also prevented by bicuculline, but unaffected by CGP. Gliotransmission in response to GABA was also unaffected by pannexin 1 channel blockade. These results are discussed in terms of the possible role of astroglial Cx43 hemichannel-mediated glutamate and ATP release in regulating the excitatory/inhibitory balance in the brain and their possible contribution to psychiatric disorders.

D-Serine Signaling and NMDAR-Mediated Synaptic Plasticity Are Regulated by System A-Type of Glutamine/D-Serine Dual Transporters.

D-serine is a physiologic coagonist of NMDA receptors (NMDARs) required for synaptic plasticity, but mechanisms that terminate D-serine signaling are unclear. In particular, the identity of unidirectional plasma membrane transporters that mediate D-serine reuptake has remained elusive. We report that D-serine and glutamine share the same neuronal transport system, consisting of the classic system A transporters Slc38a1 and Slc38a2. We show that these transporters are not saturated with glutamine in vivo and regulate the extracellular levels of D-serine and NMDAR activity. Glutamine increased the NMDAR-dependent long-term potentiation and the isolated NMDAR potentials at the Schaffer collateral-CA1 synapses, but without affecting basal neurotransmission in male mice. Glutamine did not increase the NMDAR potentials in slices from serine racemase knock-out mice, which are devoid of D-serine, indicating that the effect of glutamine is caused by outcompeting D-serine for a dual glutamine-D-serine transport system. Inhibition of the system A reduced the uptake of D-serine in synaptosomes and neuronal cultures of mice of either sex, while increasing the extracellular D-serine concentration in slices and in vivo by microdialysis. When compared with Slc38a2, the Slc38a1 transporter displayed more favorable kinetics toward the D-enantiomer. Biochemical experiments with synaptosomes from Slc38a1 knock-down mice of either sex further support its role as a D-serine reuptake system. Our study identifies the first concentrative and electrogenic transporters mediating D-serine reuptake in vivo In addition to their classical role in the glutamine-glutamate cycle, system A transporters regulate the synaptic turnover of D-serine and its effects on NMDAR synaptic plasticity.SIGNIFICANCE STATEMENT Despite the plethora of roles attributed to D-serine, the regulation of its synaptic turnover is poorly understood. We identified the system A transporters Slc38a1 and Slc38a2 as the main pathway for neuronal reuptake of D-serine. These transporters are not saturated with glutamine in vivo and provide an unexpected link between the serine shuttle pathway, responsible for regulating D-serine synaptic turnover, and the glutamine-glutamate cycle. Our observations suggest that Slc38a1 and Slc38a2 have a dual role in regulating neurotransmission. In addition to their classical role as the glutamine providers, the system A transporters regulate extracellular D-serine and therefore affect NMDAR-dependent synaptic plasticity. Higher glutamine export from astrocytes would increase extracellular D-serine, providing a feedforward mechanism to increase synaptic NMDAR activation.

Glial amplification of synaptic signals.

KEY POINTS: Recent studies have repeatedly demonstrated the cross-talk of heterogeneous signals between neuronal and glial circuits. Here, we investigated the mechanism and the influence of physiological interactions between neurons and glia in the cerebellum. We found that the cerebellar astrocytes, Bergmann glial cells, react to exogenously applied glutamate, glutamate transporter substrate (d-aspartate) and synaptically released glutamate. In response, the Bergmann glial cells release glutamate through volume-regulated anion channels. It is generally assumed that all of the postsynaptic current is mediated by presynaptically released glutamate. However, we showed that a part of the postsynaptic current is mediated by glutamate released from Bergmann glial cells. Optogenetic manipulation of Bergmann glial state with archaerhodpsin-T or channelrhodopsin-2 reduced or augmented the amount of glial glutamate release, respectively. Our data indicate that glutamate-induced glutamate release in Bergmann glia serves as an effective amplifier of excitatory information processing in the brain. ABSTRACT: Transmitter released from presynaptic neurons has been considered to be the sole generator of postsynaptic excitatory signals. However, astrocytes of the glial cell population have also been shown to release transmitter that can react on postsynaptic receptors. Therefore, we investigated whether astrocytes take part in generation of at least a part of the synaptic current. In this study, mice cerebellar acute slices were prepared and whole cell patch clamp recordings were performed. We found that Bergmann glial cells (BGs), a type of astrocyte in the cerebellum, reacts to a glutamate transporter substrate, d-aspartate (d-Asp) and an anion conductance is generated and glutamate is released from the BGs. Glutamate release was attenuated or augmented by modulating the state of BGs with activation of light-sensitive proteins, archaerhodopsin-T (ArchT) or channelrhodopsin-2 (ChR2) expressed on BGs, respectively. Glutamate release appears to be mediated by anion channels that can be blocked by a volume-regulated anion channel-specific blocker. Synaptic response to a train of parallel fibre stimulation was recorded from Purkinje cells. The latter part of the response was also attenuated or augmented by glial modulation with ArchT or ChR2, respectively. Thus, BGs effectively function as an excitatory signal amplifier, and a part of the 'synaptic' current is actually mediated by glutamate released from BGs. These data show that the state of BGs have potential for having direct and fundamental consequences on the functioning of information processing in the brain.

Astrocytic release of ATP through type 2 inositol 1,4,5-trisphosphate receptor calcium signaling and social dominance behavior in mice.

Brain mitochondrial function is critical for numerous neuronal processes. We recently identified a link between brain energy and social dominance, where higher levels of mitochondrial function resulted in increased social competitive ability. The underlying mechanism of this link, however, remains unclear. Here, we investigated the contribution of astrocytic release of adenosine triphosphate (ATP) through the type 2 inositol 1,4,5-triphosphate receptor to social dominance behavior. Mice lacking the type 2 inositol 1,4,5-triphosphate receptor were characterized for their social dominance behavior, as well as their performance on a nonsocial task, the Morris Water Maze. In parallel, we also examined mitochondrial function in the medial prefrontal cortex, nucleus accumbens, and hippocampus to investigate how deficiencies in astrocytic ATP could modulate overall mitochondrial function. While knockout mice showed similar competitive ability compared with their wild-type littermates, dominant knockout mice exhibited a significant delay in exerting their dominance during the initial encounter. Otherwise, there were no differences in anxiety and exploratory traits, spatial learning and memory, or brain mitochondrial function in either light or dark circadian phases. Our findings point to a marginal role of astrocytic ATP through IP3 R2 in social competition, suggesting that, under basal conditions, the neuronal compartment is predominant for social dominance exertion.

Sensing and Regulating Synaptic Activity by Astrocytes at Tripartite Synapse.

Astrocytes are recognized as more important cells than historically thought in synaptic function through the reciprocal exchange of signaling with the neuronal synaptic elements. The idea that astrocytes are active elements in synaptic physiology is conceptualized in the Tripartite Synapse concept. This review article presents and discusses recent representative examples that highlight the heterogeneity of signaling in tripartite synapse function and its consequences on neural network function and animal behavior.

Dysregulation of Astrocyte-Neuronal Communication in Alzheimer's Disease.

Recent studies implicate astrocytes in Alzheimer's disease (AD); however, their role in pathogenesis is poorly understood. Astrocytes have well-established functions in supportive functions such as extracellular ionic homeostasis, structural support, and neurovascular coupling. However, emerging research on astrocytic function in the healthy brain also indicates their role in regulating synaptic plasticity and neuronal excitability via the release of neuroactive substances named gliotransmitters. Here, we review how this "active" role of astrocytes at synapses could contribute to synaptic and neuronal network dysfunction and cognitive impairment in AD.

NMDARs, Coincidence Detectors of Astrocytic and Neuronal Activities.

Synaptic plasticity is an extensively studied cellular correlate of learning and memory in which NMDARs play a starring role. One of the most interesting features of NMDARs is their ability to act as a co-incident detector. It is unique amongst neurotransmitter receptors in this respect. Co-incident detection is possible because the opening of NMDARs requires membrane depolarisation and the binding of glutamate. Opening of NMDARs also requires a co-agonist. Although the dynamic regulation of glutamate and membrane depolarization have been well studied in coincident detection, the role of the co-agonist site is unexplored. It turns out that non-neuronal glial cells, astrocytes, regulate co-agonist availability, giving them the ability to influence synaptic plasticity. The unique morphology and spatial arrangement of astrocytes at the synaptic level affords them the capacity to sample and integrate information originating from unrelated synapses, regardless of any pre-synaptic and post-synaptic commonality. As astrocytes are classically considered slow responders, their influence at the synapse is widely recognized as modulatory. The aim herein is to reconsider the potential of astrocytes to participate directly in ongoing synaptic NMDAR activity and co-incident detection.