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Effective communication between different cell types is essential for brain health, and dysregulation of this process leads to neuropathologies. Brain glial cells, including microglia and astrocytes, orchestrate immune defense and neuroimmune responses under pathological conditions during which interglial communication is indispensable. Our appreciation of the complexity of these processes is rapidly increasing due to recent advances in molecular biology techniques, which have identified numerous phenotypic states of both microglia and astrocytes. This review focuses on microglia-to-astrocyte communication facilitated by secreted neuroimmune modulators. The combinations of interleukin (IL)-1α, tumor necrosis factor (TNF), plus complement component C1q as well as IL-1ß plus TNF are already well-established microglia-derived stimuli that induce reactive phenotypes in astrocytes. However, given the large number of inflammatory mediators secreted by microglia and the rapidly increasing number of distinct functional states recognized in astrocytes, it can be hypothesized that many more intercellular signaling molecules exist. This review identifies the following group of cytokines and gliotransmitters that, while not established as interglial mediators yet, are known to be released by microglia and elicit functional responses in astrocytes: IL-10, IL-12, IL-18, transforming growth factor (TGF)-ß, interferon (IFN)-γ, C-C motif chemokine ligand (CCL)5, adenosine triphosphate (ATP), l-glutamate, and prostaglandin E2 (PGE2). The review of molecular mechanisms engaged by these mediators reveals complex, partially overlapping signaling pathways implicated in numerous neuropathologies. Additionally, lack of human-specific studies is identified as a significant knowledge gap. Further research on microglia-to-astrocyte communication is warranted, as it could discover novel interglial signaling-targeted therapies for diverse neurological disorders.

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Windows of plasticity allow environmental experiences to produce intense activity-dependent changes during postnatal development. The reordering and refinement of neural connections occurs during these periods, significantly influencing the formation of brain circuits and physiological processes in adults. Recent advances have shed light on factors that determine the onset and duration of sensitive and critical periods of plasticity. Although GABAergic inhibition has classically been implicated in closing windows of plasticity, astrocytes and adenosinergic inhibition have also emerged more recently as key determinants of the duration of these periods of plasticity. Here, we review novel aspects of the involvement of GABAergic inhibition, the possible role of presynaptic NMDARs, and the emerging roles of astrocytes and adenosinergic inhibition in determining the duration of windows of plasticity in different brain regions.

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Understanding neuronal firing patterns and long-term potentiation (LTP) induction in studying learning, memory, and neurological diseases is critical. However, recently, despite the rapid advancement in neuroscience, we are still constrained by the experimental design, detection tools for exploring the mechanisms and pathways involved in LTP induction, and detection ability of neuronal action potentiation signals. This review will reiterate LTP-related electrophysiological recordings in the mammalian brain for nearly 50 years and explain how excitatory and inhibitory neural LTP results have been detected and described by field- and single-cell potentials, respectively. Furthermore, we focus on describing the classic model of LTP of inhibition and discuss the inhibitory neuron activity when excitatory neurons are activated to induce LTP. Finally, we propose recording excitatory and inhibitory neurons under the same experimental conditions by combining various electrophysiological technologies and novel design suggestions for future research. We discussed different types of synaptic plasticity, and the potential of astrocytes to induce LTP also deserves to be explored in the future.

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Butyrate and indole-3-propionic acid represent the CNS-available gut microbiota metabolites exhibiting potentially beneficial effects on human brain function and being tested as antidepressants. Astrocytes represent one of the putative targets for the gut metabolites; however, the mechanism of action of butyrate and indole-3-propionic acid is not well understood. In order to test this mechanism, a human astrocyte cell-line culture was treated with the compounds or without them, and the supernatants were collected for the analysis of ATP and glutamate gliotransmitter release with the use of luminescent and fluorescent methods, respectively. A 10-min incubation of astrocytes with 1-5 mM butyrate increased the ATP gliotransmitter release by 78% (95%CI: 45-119%), p < 0.001. The effect was found to be mediated by the cytosolic Ca2+ mobilization. Both 10-min and 24-h treatments with indole-3-propionic acid produced no significant effects on the release of gliotransmitters. The results for glutamate release were inconclusive due to a specific glutamate release pattern discovered in the tested model. This preliminary report of butyrate-induced ATP gliotransmitter release appears to provide a novel mechanistic explanation for the beneficial effect of this gut microbiota metabolite on brain function; however, the results require further evaluation in more composed models.

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Although ATP and/or adenosine derived from astrocytes are known to regulate sleep, the precise mechanisms underlying the somnogenic effects of ATP and adenosine remain unclear. We selectively expressed channelrhodopsin-2 (ChR2), a light-sensitive ion channel, in astrocytes within the ventrolateral preoptic nucleus (VLPO), which is an essential brain nucleus involved in sleep promotion. We then examined the effects of photostimulation of astrocytic ChR2 on neuronal excitability using whole-cell patch-clamp recordings in two functionally distinct types of VLPO neurons: sleep-promoting GABAergic projection neurons and non-sleep-promoting local GABAergic neurons. Optogenetic stimulation of VLPO astrocytes demonstrated opposite outcomes in the two types of VLPO neurons. It led to the inhibition of non-sleep-promoting neurons and excitation of sleep-promoting neurons. These responses were attenuated by blocking of either adenosine A1 receptors or tissue-nonspecific alkaline phosphatase (TNAP). In contrast, exogenous adenosine decreased the excitability of both VLPO neuron populations. Moreover, TNAP was expressed in galanin-negative VLPO neurons, but not in galanin-positive sleep-promoting projection neurons. Taken together, these results suggest that astrocyte-derived ATP is converted into adenosine by TNAP in non-sleep-promoting neurons. In turn, adenosine decreases the excitability of local GABAergic neurons, thereby increasing the excitability of sleep-promoting GABAergic projection neurons. We propose a novel mechanism involving astrocyte-neuron interactions in sleep regulation, wherein endogenous adenosine derived from astrocytes excites sleep-promoting VLPO neurons, and thus decreases neuronal excitability in arousal-related areas of the brain.

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Anxiety involves abnormal glucocorticoid signalling and altered glia-neuron communication in brain regions processing emotional responses. Adenosine A2A receptor (A2AR) blockade ameliorates mood and memory impairments by preventing synaptic dysfunction and astrogliosis. Since the glucocorticoid dexamethasone (DEX) can mimic early life-stress conditions, leading to anxiety-like behaviours, we now tested if A2AR blockade prevents alterations in the morphology and function of astrocytes exposed to DEX. Cultured astrocytes exposed to DEX exhibited an up-regulation of astrocytic markers (GFAP, connexin-43 and glutamine synthetase), as well as of A2AR. Moreover, DEX enhanced ATP and glutamate release and increased basal astrocytic Ca2+ levels. The selective A2AR antagonist SCH58261 prevented DEX-induced alterations in ATP release and basal Ca2+ levels but did not affect DEX-induced alteration of glutamate release and astrocytic markers. These findings suggest that alterations in astrocytes function, which might contribute to abnormal glucocorticoid brain signalling, are controlled by A2AR, and therefore, reinforce the relevance of A2AR as a potential therapeutic target to manage mood disorders.

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Astrocytes were traditionally regarded as cells important to neuronal activity, providing both metabolic and structural supports. Recent evidence suggests that they may also play a crucial role in the control of higher brain functions. In keeping with this hypothesis, it is now well accepted that astrocytes contribute to stress but also react to antidepressant drugs as they express serotonergic transporters and receptors. However, the downstream mechanisms leading to the fine-tuned regulation of mood are still unknown. This chapter pays attention to the role of astrocytes in the regulation of emotional behavior and related serotonergic neurotransmission. In particular, it gives a current state of the clinical and preclinical evidence showing that astrocytes respond to environmental conditions and antidepressant drugs through the release of gliotransmitters and neurotrophic factors which in turn, influence serotonergic tone in discrete brain areas. This state-of-the-art review aims at demonstrating the remarkable potential for novel therapeutic antidepressant strategies targeting these glial cells.

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Astrocytes, a major type of glial cell, are known to play key supportive roles in brain function, contributing to ion and neurotransmitter homeostasis, maintaining the blood-brain barrier and providing trophic and metabolic support for neurons. Besides these support functions, astrocytes are emerging as important elements in brain physiology through signaling exchange with neurons at tripartite synapses. Astrocytes express a wide variety of neurotransmitter transporters and receptors that allow them to sense and respond to synaptic activity. Principal among them are the G-protein-coupled receptors (GPCRs) in astrocytes because their activation by synaptically released neurotransmitters leads to mobilization of intracellular calcium. In turn, activated astrocytes release neuroactive substances called gliotransmitters, such as glutamate, GABA, and ATP/adenosine that lead to synaptic regulation through activation of neuronal GPCRs. In this review we will present and discuss recent evidence demonstrating the critical roles played by GPCRs in the bidirectional astrocyte-neuron signaling, and their crucial involvement in the astrocyte-mediated regulation of synaptic transmission and plasticity.

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Although ventrolateral preoptic (VLPO) nucleus is regarded as a center for sleep promotion, the exact mechanisms underlying the sleep regulation are unknown. Here, we used optogenetic tools to identify the key roles of VLPO astrocytes in sleep promotion. Optogenetic stimulation of VLPO astrocytes increased sleep duration in the active phase in naturally sleep-waking adult male rats (n = 6); it also increased the extracellular ATP concentration (n = 3) and c-Fos expression (n = 3-4) in neurons within the VLPO. In vivo microdialysis analyses revealed an increase in the activity of VLPO astrocytes and ATP levels during sleep states (n = 4). Moreover, metabolic inhibition of VLPO astrocytes reduced ATP levels (n = 4) and diminished sleep duration (n = 4). We further show that tissue-nonspecific alkaline phosphatase (TNAP), an ATP-degrading enzyme, plays a key role in mediating the somnogenic effects of ATP released from astrocytes (n = 5). An appropriate sample size for all experiments was based on statistical power calculations. Our results, taken together, indicate that astrocyte-derived ATP may be hydrolyzed into adenosine by TNAP, which may in turn act on VLPO neurons to promote sleep.SIGNIFICANCE STATEMENT Glia have recently been at the forefront of neuroscience research. Emerging evidence illustrates that astrocytes, the most abundant glial cell type, are the functional determinants for fates of neurons and other glial cells in the central nervous system. In this study, we newly identified the pivotal role of hypothalamic ventrolateral preoptic (VLPO) astrocytes in the sleep regulation, and provide novel insights into the mechanisms underlying the astrocyte-mediated sleep regulation.

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Connexins (Cxs) are a family of 21 protein isoforms, eleven of which are expressed in the central nervous system, and they are found in neurons and glia. Cxs form hemichannels (connexons) and channels (gap junctions/electric synapses) that permit functional and metabolic coupling between neurons and astrocytes. Altered Cx expression and function is involved in inflammation and neurological diseases. Cxs-based hemichannels and channels have a relevance to seizures and epilepsy in two ways: First, this pathological condition increases the opening probability of hemichannels in glial cells to enable gliotransmitter release, sustaining the inflammatory process and exacerbating seizure generation and epileptogenesis, and second, the opening of channels favors excitability and synchronization through coupled neurons. These biological events highlight the global pathological mechanism of epilepsy, and the therapeutic potential of Cxs-based hemichannels and channels. Therefore, this review describes the role of Cxs in neuroinflammation and epilepsy and examines how the blocking of channels and hemichannels may be therapeutic targets of anti-convulsive and anti-epileptic treatments.

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Mood disorders have multiple phenotypes and complex underlying biological mechanisms and, as such, there are no effective therapeutic strategies. A review of recent work on the role of astrocytes in mood disorders is thus warranted, which we embark on here. We argue that there is tremendous potential for novel strategies for therapeutic interventions based on the role of astrocytes. Astrocytes are traditionally considered to have supporting roles within the brain, yet emerging evidence has shown that astrocytes have more direct roles in influencing brain function. Notably, evidence from postmortem human brain tissues has highlighted changes in glial cell morphology, density and astrocyte-related biomarkers and genes following mood disorders, indicating astrocyte involvement in mood disorders. Findings from animal models strongly imply that astrocytes not only change astrocyte morphology and physiological characteristics but also influence neural circuits via synapse structure and formation. This review pays particular attention to interactions between astrocytes and neurons and argues that astrocyte dysfunction affects the monoaminergic system, excitatory-inhibitory balance and neurotrophic states of local networks. Together, these studies provide a foundation of knowledge about the exact role of astrocytes in mood disorders. Importantly, we then change the focus from neurons to glial cells and the interactions between the two, so that we can understand newly proposed mechanisms underlying mood disorders, and to identify more diagnostic indicators or effective targets for treatment of these diseases.

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Gonadotropin-releasing hormone (GnRH) neuron activity and GnRH secretion are essential for fertility in mammals. Here, I review findings from mouse studies on the direct modulation of GnRH neuron activity and GnRH secretion by non-peptide neurotransmitters (GABA, glutamate, dopamine, serotonin, norepinephrine, epinephrine, histamine, ATP, adenosine, and acetylcholine), gasotransmitters (nitric oxide and carbon monoxide), and gliotransmitters (prostaglandin E2 and possibly GABA, glutamate, and ATP). These neurotransmitters, gasotransmitters, and gliotransmitters have been shown to directly modulate activity and/or GnRH secretion in GnRH neurons in vivo or ex vivo (brain slices), from postnatal through adult mice, or in embryonic or immortalized mouse GnRH neurons. However, except for GABA, nitric oxide, and prostaglandin E2, which appear to be essential for normal GnRH neuron activity, GnRH secretion, and fertility in males and/or females, the biological significance of their direct modulation of GnRH neuron activity and/or GnRH secretion in the central regulation of reproduction remains largely unknown and requires further exploration.

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Astrocytes are heterogeneous cells of the central nervous system whose uptake of neurotransmitters and neuromodulators can influence synaptic signaling. Any malfunction in this process can lead to serious defects in synaptic transmission found in, for example, neurodegenerative diseases like Alzheimer's or epilepsy.Here we describe how to visualize the uptake of an extracellularly located protein by in vitro cultured astrocytes on the example of tissue plasminogen activator, a serine protease tightly involved in long-term potentiation and seizure generation.

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In this review article, we summarize the current insight on the role of Connexin- and Pannexin-based channels as modulators of sensory neurons. The somas of sensory neurons are located in sensory ganglia (i.e., trigeminal and nodose ganglia). It is well known that within sensory ganglia, sensory neurons do not form neither electrical nor chemical synapses. One of the reasons for this is that each soma is surrounded by glial cells, known as satellite glial cells (SGCs). Recent evidence shows that connexin43 (Cx43) hemichannels and probably pannexons located at SGCs have an important role in paracrine communication between glial cells and sensory neurons. This communication may be exerted via the release of bioactive molecules from SGCs and their subsequent action on receptors located at the soma of sensory neurons. The glio-neuronal communication seems to be relevant for the establishment of chronic pain, hyperalgesia and pathologies associated with tissue inflammation. Based on the current literature, it is possible to propose that Cx43 hemichannels expressed in SGCs could be a novel pharmacological target for treating chronic pain, which need to be directly evaluated in future studies.

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Under physiological conditions, microglia adopt a resting phenotype associated with the production of anti-inflammatory and neurotrophic factors. In response to a wide variety of insults, these cells shift to an activated phenotype that is necessary for the proper restoration of brain homeostasis. However, when the intensity of a threat is relatively high, microglial activation worsens the progression of damage rather than providing protection, with potentially significant consequences for neuronal survival. Coordinated interactions among microglia and other brain cells, including astrocytes and neurons, are critical for the development of timely and optimal inflammatory responses in the brain parenchyma. Tissue synchronization is in part mediated by connexins and pannexins, which are protein families that form different plasma membrane channels to communicate with neighboring cells. Gap junction channels (which are exclusively formed by connexins in vertebrates) connect the cytoplasm of contacting cells to coordinate electrical and metabolic coupling. Hemichannels (HCs) and pannexons (which are formed by connexins and pannexins, respectively) communicate the intra- and extracellular compartments and serve as diffusion pathways for the exchange of ions and small molecules. In this review article, we discuss the available evidence concerning the functional expression and regulation of connexin- and pannexin-based channels in microglia and their contributions to microglial function and dysfunction. Specifically, we focus on the possible implications of these channels in microglia-to-microglia, microglia-to-astrocyte and neuron-to-microglia interactions in the inflamed brain.

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The brain performs exceptionally complex and dynamic tasks that depend on the coordinated interaction of neurons, glial cells, endothelial cells, pericytes, smooth muscle cells, ependymal cells, and circulating blood cells. Among these cells, glial cells have emerged as crucial protagonists in the regulation of synaptic transmission and neural function. Indeed, these cells express a wide range of receptors that enable them to sense changes in neuronal activity and the microenvironment by responding locally via the release of bioactive molecules known as gliotransmitters. In the central nervous system (CNS), a novel mechanism that allows gliotransmission via the opening of hemichannels has been proposed. These channels are composed of six protein subunits consisting of connexins or pannexins, which are two highly conserved protein families that are encoded by 21 and 3 genes, respectively, in humans. Typically, glial cell hemichannels exhibit low levels of activity, but this activity is sufficient to ensure the release of a broad spectrum of gliotransmitters, including ATP, D-serine, glutamate, adenosine, and glutathione. Here, we briefly review the current findings regarding the effects of the hemichannel-dependent release of gliotransmitters on the physiology of the CNS.

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Astrocytes perform various homeostatic functions in the nervous system beyond that of a supportive or metabolic role for neurons. A growing body of evidence indicates that astrocytes are crucial for central respiratory chemoreception. This review presents a classical overview of respiratory central chemoreception and the new evidence for astrocytes as brainstem sensors in the respiratory response to hypercapnia. We review properties of astrocytes for chemosensory function and for modulation of the respiratory network. We propose that astrocytes not only mediate between CO2/H+ levels and motor responses, but they also allow for two emergent functions: (1) Amplifying the responses of intrinsic chemosensitive neurons through feedforward signaling via gliotransmitters and; (2) Recruiting non-intrinsically chemosensitive cells thanks to volume spreading of signals (calcium waves and gliotransmitters) to regions distant from the CO2/H+ sensitive domains. Thus, astrocytes may both increase the intensity of the neuron responses at the chemosensitive sites and recruit of a greater number of respiratory neurons to participate in the response to hypercapnia.

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Key support for vesicle-based release of gliotransmitters comes from studies of transgenic mice with astrocyte-specific expression of a dominant-negative domain of synaptobrevin 2 protein (dnSNARE). To determine how this peptide affects exocytosis, we used super-resolution stimulated emission depletion microscopy and structured illumination microscopy to study the anatomy of single vesicles in astrocytes. Smaller vesicles contained amino acid and peptidergic transmitters and larger vesicles contained ATP. Discrete increases in membrane capacitance, indicating single-vesicle fusion, revealed that astrocyte stimulation increases the frequency of predominantly transient fusion events in smaller vesicles, whereas larger vesicles transitioned to full fusion. To determine whether this reflects a lower density of SNARE proteins in larger vesicles, we treated astrocytes with botulinum neurotoxins D and E, which reduced exocytotic events of both vesicle types. dnSNARE peptide stabilized the fusion-pore diameter to narrow, release-unproductive diameters in both vesicle types, regardless of vesicle diameter.

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Astrocytes are multitasking players in brain complexity, possessing several receptors and mechanisms to detect, participate and modulate neuronal communication. The functionality of astrocytes has been mainly unraveled through the study of primary astrocyte cultures, and recently our research group characterized a model of astrocyte cultures derived from adult Wistar rats. We, herein, aim to characterize other basal functions of these cells to explore the potential of this model for studying the adult brain. To characterize the astrocytic phenotype, we determined the presence of GFAP, GLAST and GLT 1 proteins in cells by immunofluorescence. Next, we determined the concentrations of thirteen amino acids, ATP, ADP, adenosine and calcium in astrocyte cultures, as well as the activities of Na(+)/K(+)-ATPase and acetylcholine esterase. Furthermore, we assessed the presence of the GABA transporter 1 (GAT 1) and cannabinoid receptor 1 (CB 1) in the astrocytes. Cells demonstrated the presence of glutamine, consistent with their role in the glutamate-glutamine cycle, as well as glutamate and D-serine, amino acids classically known to act as gliotransmitters. ATP was produced and released by the cells and ADP was consumed. Calcium levels were in agreement with those reported in the literature, as were the enzymatic activities measured. The presence of GAT 1 was detected, but the presence of CB 1 was not, suggesting a decreased neuroprotective capacity in adult astrocytes under in vitro conditions. Taken together, our results show cellular functionality regarding the astrocytic role in gliotransmission and neurotransmitter management since they are able to produce and release gliotransmitters and to modulate the cholinergic and GABAergic systems.

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