Circadian Rhythms and Astrocytes: The Good, the Bad, and the Ugly.

This review explores the interface between circadian timekeeping and the regulation of brain function by astrocytes. Although astrocytes regulate neuronal activity across many time domains, their cell-autonomous circadian clocks exert a particular role in controlling longer-term oscillations of brain function: the maintenance of sleep states and the circadian ordering of sleep and wakefulness. This is most evident in the central circadian pacemaker, the suprachiasmatic nucleus, where the molecular clock of astrocytes suffices to drive daily cycles of neuronal activity and behavior. In Alzheimer's disease, sleep impairments accompany cognitive decline. In mouse models of the disease, circadian disturbances accelerate astroglial activation and other brain pathologies, suggesting that daily functions in astrocytes protect neuronal homeostasis. In brain cancer, treatment in the morning has been associated with prolonged survival, and gliomas have daily rhythms in gene expression and drug sensitivity. Thus, circadian time is fast becoming critical to elucidating reciprocal astrocytic-neuronal interactions in health and disease.

Emerging evidence for astrocyte dysfunction in schizophrenia.

Schizophrenia is a complex, chronic mental health disorder whose heterogeneous genetic and neurobiological background influences early brain development, and whose precise etiology is still poorly understood. Schizophrenia is not characterized by gross brain pathology, but involves subtle pathological changes in neuronal populations and glial cells. Among the latter, astrocytes critically contribute to the regulation of early neurodevelopmental processes, and any dysfunctions in their morphological and functional maturation may lead to aberrant neurodevelopmental processes involved in the pathogenesis of schizophrenia, such as mitochondrial biogenesis, synaptogenesis, and glutamatergic and dopaminergic transmission. Studies of the mechanisms regulating astrocyte maturation may therefore improve our understanding of the cellular and molecular mechanisms underlying the pathogenesis of schizophrenia.

Pannexin-1 in the CNS: Emerging concepts in health and disease.

Pannexin-1 (Panx1) is a large pore membrane channel with unique conduction properties ranging from non-selective ion permeability to the extracellular release of signalling molecules. The release of ATP by Panx1 has been particularly well-characterized with implications in purine signalling across a variety of biological contexts. Panx1 activity is also important in inflammasome formation and the secretion of pro-inflammatory molecules such as interleukin-1ß. Within the central nervous system (CNS), Panx1 is expressed on both neurons and glia, and is thought to mediate crosstalk between these cells. A growing body of literature now supports the pathological activity of Panx1 in contributing to disease processes including seizure, stroke, migraine headache and chronic pain. Emerging evidence also reveals a physiological function of Panx1 in regulating neural stem cell survival, neuronal maturation and synaptic plasticity, with possible relevance to normal cognitive functioning. The aim of this review is to summarize the current evidence regarding the roles of Panx1 in the CNS, with emphasis on how putative signalling properties and activation mechanisms of this channel contribute to various physiological and pathophysiological processes.

Evidence for astrocyte purinergic signaling in cortical sensory adaptation and serotonin-mediated neuromodulation.

In the somatosensory cortex, inhibitory networks are involved in low frequency sensory input adaptation/habituation that can be observed as a paired-pulse depression when using a dual stimulus electrophysiological paradigm. Given that astrocytes have been shown to regulate inhibitory interneuron activity, we hypothesized that astrocytes are involved in cortical sensory adaptation/habituation and constitute effectors of the 5HT-mediated increase in frequency transmission. Using extracellular recordings of evoked excitatory postsynaptic potentials (eEPSPs) in layer II/III of somatosensory cortex, we used various pharmacological approaches to assess the recruitment of astrocyte signaling in paired-pulse depression and serotonin-mediated increase in the paired-pulse ratio (pulse 2/pulse 1). In the absence of neuromodulators or pharmacological agents, the first eEPSP is much larger in amplitude than the second due to the recruitment of long-lasting evoked GABAA-dependent inhibitory activity from the first stimulus. Disruption of glycolysis or mGluR5 signaling resulted in a very similar loss of paired-pulse depression in field recordings. Interestingly, paired-pulse depression was similarly sensitive to disruption by ATP P2Y and adenosine A2A receptor antagonists. In addition, we show that pharmacological disruption of paired-pulse depression by mGluR5, P2Y, and glycolysis inhibition precluded serotonin effects on frequency transmission (typically increased the paired-pulse ratio). These data highlight the possibility for astrocyte involvement in cortical inhibitory activity seen in this simple cortical network and that serotonin may act on astrocytes to exert some aspects of its modulatory influence.

Contribution of Astroglial Cx43 Hemichannels to the Modulation of Glutamatergic Currents by D-Serine in the Mouse Prefrontal Cortex.

Astrocytes interact dynamically with neurons by modifying synaptic activity and plasticity. This interplay occurs through a process named gliotransmission, meaning that neuroactive molecules are released by astrocytes. Acting as a gliotransmitter, D-serine, a co-agonist of the NMDA receptor at the glycine-binding site, can be released by astrocytes in a calcium [Ca2+]i-dependent manner. A typical feature of astrocytes is their high expression level of connexin43 (Cx43), a protein forming gap junction channels and hemichannels associated with dynamic neuroglial interactions. Pharmacological and genetic inhibition of Cx43 hemichannel activity reduced the amplitude of NMDA EPSCs in mouse layer 5 prefrontal cortex pyramidal neurons without affecting AMPA EPSC currents. This reduction of NMDA EPSCs was rescued by addition of D-serine in the extracellular medium. LTP of NMDA and AMPA EPSCs after high-frequency stimulation was reduced by prior inhibition of Cx43 hemichannel activity. Inactivation of D-serine synthesis within the astroglial network resulted in the reduction of NMDA EPSCs, which was rescued by adding extracellular D-serine. We showed that the activity of Cx43 hemichannels recorded in cultured astrocytes was [Ca2+]I dependent. Accordingly, in acute cortical slices, clamping [Ca2+]i at a low level in astroglial network resulted in an inhibition of NMDA EPSC potentiation that was rescued by adding extracellular D-serine. This work demonstrates that astroglial Cx43 hemichannel activity is associated with D-serine release. This process, occurring by direct permeation of D-serine through hemichannels or indirectly by Ca2+ entry and activation of other [Ca2+]i-dependent mechanisms results in the modulation of synaptic activity and plasticity.SIGNIFICANCE STATEMENT We recorded neuronal glutamatergic (NMDA and AMPA) responses in prefrontal cortex (PFC) neurons and used pharmacological and genetic interventions to block connexin-mediated hemichannel activity specifically in a glial cell population. For the first time in astrocytes, we demonstrated that hemichannel activity depends on the intracellular calcium concentration and is associated with D-serine release. Blocking hemichannel activity reduced the LTP of these excitatory synaptic currents triggered by high-frequency stimulation. These observations may be particularly relevant in the PFC, where D-serine and its converting enzyme are highly expressed.

The Schwann Cell as an Active Synaptic Partner.

The schwann cells of the peripheral nervous system are indispensable for the formation, maintenance, and modulation of synapses over the life cycle. They not only recognize neuron-glia signaling molecules, but also secrete gliotransmitters. Through these processes, they regulate neuronal excitability and thus the release of neurotransmitters from the nerve terminal at the neuromuscular junction. Gliotransmitters strongly affect nerve communication, and their secretion is mainly triggered by synchronized Ca2+ signaling, implicating Ca2+ waves in synapse function. Reciprocally, neurotransmitters released during synaptic activity can evoke increases in intracellular Ca2+ levels. A reconsideration of the interplay between the two main types of cells in the nervous system is due, as the concept of nervous system activity comprising only neuron-neuron and neuron-muscle action has become untenable. A more precise understanding of the roles of schwann cells in nerve-muscle signaling is required.

Histamine elicits glutamate release from cultured astrocytes.

Astrocytes play key roles in regulating brain homeostasis and neuronal activity. This is, in part, accomplished by the ability of neurotransmitters in the synaptic cleft to bind astrocyte membrane receptors, activating signalling cascades that regulate concentration of intracellular Ca2+ ([Ca2+]i) and gliotransmitter release, including ATP and glutamate. Gliotransmitters contribute to dendrite formation and synaptic plasticity, and in some cases, exacerbate neurodegeneration. The neurotransmitter histamine participates in several physiological processes, such as the sleep-wake cycle and learning and memory. Previous studies have demonstrated the expression of histamine receptors on astrocytes, but until now, only a few studies have examined the effects of histamine on astrocyte intracellular signalling and gliotransmitter release. Here, we used the human astrocytoma cell line 1321N1 to study the role of histamine in astrocyte intracellular signalling and gliotransmitter release. We found that histamine activated astrocyte signalling through histamine H1 and H2 receptors, leading to distinct cellular responses. Activation of histamine H1 receptors caused concentration-dependent release of [Ca2+]i from internal stores and concentration-dependent increase in glutamate release. Histamine H2 receptor activation increased cyclic adenosine monophosphate (cAMP) levels and phosphorylation of transcription factor cAMP response-element binding protein. Taken together, these data emphasize a role for histamine in neuron-glia communication.

Suppression of SNARE-dependent exocytosis in retinal glial cells and its effect on ischemia-induced neurodegeneration.

Nervous tissue is characterized by a tight structural association between glial cells and neurons. It is well known that glial cells support neuronal functions, but their role under pathologic conditions is less well understood. Here, we addressed this question in vivo using an experimental model of retinal ischemia and transgenic mice for glia-specific inhibition of soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE)-dependent exocytosis. Transgene expression reduced glutamate, but not ATP release from single Müller cells, impaired glial volume regulation under normal conditions and reduced neuronal dysfunction and death in the inner retina during the early stages of ischemia. Our study reveals that the SNARE-dependent exocytosis in glial cells contributes to neurotoxicity during ischemia in vivo and suggests glial exocytosis as a target for therapeutic approaches.

An astroglial basis of major depressive disorder? An overview.

Depression is a chronic, recurring, and serious mood disorder that afflicts up to 20% of the global population. The monoamine hypothesis has dominated our understanding of the pharmacotherapy of depression for more than half a century; however, our understanding of the pathophysiology and pathogenesis of major depression has lagged far behind. Astrocytes are the most abundant and versatile cells in the brain, participating in most, if not all, of brain functions as both a passive housekeeper and an active player. Mounting evidence from clinical, preclinical and post-mortem studies has revealed a decrease in the number or density of astrocytes and morphological and functional astroglial atrophy in patients with major depressive disorder (MDD) and in animal models of depression. Furthermore, currently available antidepressant treatments at least partially exert their therapeutic effects on astrocytes. More importantly, dysfunctional astrocytes lead to depressive-like phenotypes in animals. Together, current studies point to astroglial pathology as the potential root cause of MDD. Thus, a shift from a neuron-centric to an astrocyte-centric cause of MDD has gained increasing attention during the past two decades. Here we will summarize the current evidence supporting the hypothesis that MDD is a disease of astrocyte pathology and highlight previous studies on promising strategies that directly target astrocytes for the development of novel antidepressant treatments.

Glycine release from astrocytes via functional reversal of GlyT1.

It was previously reported that functional glycine receptors were expressed in neonatal prefrontal cortex; however, the glycine-releasing cells were unknown. We hypothesized that astrocytes might be a major glycine source, and examined the glycine release properties of astrocytes. We also hypothesized that dopamine (DA) might be a trigger for the astrocytic glycine release, as numerous DA terminals localize in the cortex. We combined two different methods to confirm the glycine release from astrocytes. Firstly, we analyzed the supernatant of astrocytes by amino acid analyzer after DA stimulation, and detect significant glycine peak. Furthermore, we utilized a patch-clamp biosensor method to confirm the glycine release from astrocytes by using GlyRα1 and Glyß-expressing HEK293T cells, and detected significant glycine-evoked current upon DA stimulation. Thus, we clearly demonstrated that DA induces glycine release from astrocytes. Surprisingly, DA caused a functional reversal of astrocytic glycine transporter 1, an astrocytic type of glycine transporter, causing astrocytes to release glycine. Hence, astrocytes transduce pre-synaptic DA signals to glycine signals through a reversal of astrocytic glycine transporter 1 to regulate neuronal excitability. Cover Image for this issue: doi: 10.1111/jnc.13785.

Severe Convulsions and Dysmyelination in Both Jimpy and Cx32/47 -/- Mice may Associate Astrocytic L-Channel Function with Myelination and Oligodendrocytic Connexins with Internodal Kv Channels.

The Jimpy mouse illustrates the importance of interactions between astrocytes and oligodendrocytes. It has a mutation in Plp coding for proteolipid protein and DM20. Its behavior is normal at birth but from the age of ~2 weeks it shows severe convulsions associated with oligodendrocyte/myelination deficits and early death. A normally occurring increase in oxygen consumption by highly elevated K+ concentrations is absent in Jimpy brain slices and cultured astrocytes, reflecting that Plp at early embryonic stages affects common precursors as also shown by the ability of conditioned medium from normal astrocytes to counteract histological abnormalities. This metabolic response is now known to reflect opening of L-channels for Ca2+. The resulting deficiency in Ca2+ entry has many consequences, including lack of K+-stimulated glycogenolysis and release of gliotransmitter ATP. Lack of purinergic stimulation compromises oligodendrocyte survival and myelination and affects connexins and K+ channels. Mice lacking the oligodendrocytic connexins Cx32 and 47 show similar neurological dysfunction as Jimpy. This possibly reflects that K+ released by intermodal axonal Kv channels is transported underneath a loosened myelin sheath instead of reaching the extracellular space via connexin-mediated transport to oligodendrocytes, followed by release and astrocytic Na+,K+-ATPase-driven uptake with subsequent Kir4.1-facilitated release and neuronal uptake.

Astrocytes contribute to gamma oscillations and recognition memory.

Glial cells are an integral part of functional communication in the brain. Here we show that astrocytes contribute to the fast dynamics of neural circuits that underlie normal cognitive behaviors. In particular, we found that the selective expression of tetanus neurotoxin (TeNT) in astrocytes significantly reduced the duration of carbachol-induced gamma oscillations in hippocampal slices. These data prompted us to develop a novel transgenic mouse model, specifically with inducible tetanus toxin expression in astrocytes. In this in vivo model, we found evidence of a marked decrease in electroencephalographic (EEG) power in the gamma frequency range in awake-behaving mice, whereas neuronal synaptic activity remained intact. The reduction in cortical gamma oscillations was accompanied by impaired behavioral performance in the novel object recognition test, whereas other forms of memory, including working memory and fear conditioning, remained unchanged. These results support a key role for gamma oscillations in recognition memory. Both EEG alterations and behavioral deficits in novel object recognition were reversed by suppression of tetanus toxin expression. These data reveal an unexpected role for astrocytes as essential contributors to information processing and cognitive behavior.

PAR1-activated astrocytes in the nucleus of the solitary tract stimulate adjacent neurons via NMDA receptors.

Severe autonomic dysfunction, including the loss of control of the cardiovascular, respiratory, and gastrointestinal systems, is a common comorbidity of stroke and other bleeding head injuries. Previous studies suggest that this collapse of autonomic control may be caused by thrombin acting on astrocytic protease-activated receptors (PAR1) in the hindbrain. Using calcium imaging and electrophysiological techniques, we evaluated the mechanisms by which astrocytic PAR1s modulate the activity of presynaptic vagal afferent terminals and postsynaptic neurons in the rat nucleus of the solitary tract (NST). Our calcium-imaging data show that astrocytic and neuronal calcium levels increase after brain slices are treated with the PAR1 agonist SFLLRN-NH2. This increase in activity is blocked by pretreating the slices with the glial metabolic blocker fluorocitrate. In addition, PAR1-activated astrocytes communicate directly with NST neurons by releasing glutamate. Calcium responses to SFLLRN-NH2 in the astrocytes and neurons significantly increase after bath application of the excitatory amino acid transporter blocker DL-threo-ß-benzyloxyaspartic acid (TBOA) and significantly decrease after bath application of the NMDA receptor antagonist DL-2-amino-5-phosphonopentanoic acid (DL-AP5). Furthermore, astrocytic glutamate activates neuronal GluN2B-containing NMDA receptors. Voltage-clamp recordings of miniature EPSCs (mEPSCs) from NST neurons show that astrocytes control presynaptic vagal afferent excitability directly under resting and activated conditions. Fluorocitrate significantly decreases mEPSC frequency and SFLLRN-NH2 significantly increases mEPSC frequency. These data show that astrocytes act within a tripartite synapse in the NST, controlling the excitability of both postsynaptic NST neurons and presynaptic vagal afferent terminals.

Role of inorganic polyphosphate in mammalian cells: from signal transduction and mitochondrial metabolism to cell death.

Inorganic polyphosphate (polyP) is a polymer compromised of linearly arranged orthophosphate units that are linked through high-energy phosphoanhydride bonds. The chain length of this polymer varies from five to several thousand orthophosphates. PolyP is distributed in the most of the living organisms and plays multiple functions in mammalian cells, it is important for blood coagulation, cancer, calcium precipitation, immune response and many others. Essential role of polyP is shown for mitochondria, from implication into energy metabolism and mitochondrial calcium handling to activation of permeability transition pore (PTP) and cell death. PolyP is a gliotransmitter which transmits the signal in astrocytes via activation of P2Y1 receptors and stimulation of phospholipase C. PolyP-induced calcium signal in astrocytes can be stimulated by different lengths of this polymer but only long chain polyP induces mitochondrial depolarization by inhibition of respiration and opening of the PTP. It leads to induction of astrocytic cell death which can be prevented by inhibition of PTP with cyclosporine A. Thus, medium- and short-length polyP plays role in signal transduction and mitochondrial metabolism of astrocytes and long chain of this polymer can be toxic for the cells.

A novel subtype of astrocytes expressing TRPV4 (transient receptor potential vanilloid 4) regulates neuronal excitability via release of gliotransmitters.

Astrocytes play active roles in the regulation of synaptic transmission. Neuronal excitation can evoke Ca(2+) transients in astrocytes, and these Ca(2+) transients can modulate neuronal excitability. Although only a subset of astrocytes appears to communicate with neurons, the types of astrocytes that can regulate neuronal excitability are poorly characterized. We found that ∼30% of astrocytes in the brain express transient receptor potential vanilloid 4 (TRPV4), indicating that astrocytic subtypes can be classified on the basis of their expression patterns. When TRPV4(+) astrocytes are activated by ligands such as arachidonic acid, the activation propagates to neighboring astrocytes through gap junctions and by ATP release from the TRPV4(+) astrocytes. After activation, both TRPV4(+) and TRPV4(-) astrocytes release glutamate, which acts as an excitatory gliotransmitter to increase synaptic transmission through type 1 metabotropic glutamate receptor (mGluR). Our results indicate that TRPV4(+) astrocytes constitute a novel subtype of the population and are solely responsible for initiating excitatory gliotransmitter release to enhance synaptic transmission. We propose that TRPV4(+) astrocytes form a core of excitatory glial assembly in the brain and function to efficiently increase neuronal excitation in response to endogenous TRPV4 ligands.

Effects of ketone bodies in Alzheimer's disease in relation to neural hypometabolism, ß-amyloid toxicity, and astrocyte function.

Diet supplementation with ketone bodies (acetoacetate and ß-hydroxybuturate) or medium-length fatty acids generating ketone bodies has consistently been found to cause modest improvement of mental function in Alzheimer's patients. It was suggested that the therapeutic effect might be more pronounced if treatment was begun at a pre-clinical stage of the disease instead of well after its manifestation. The pre-clinical stage is characterized by decade-long glucose hypometabolism in brain, but ketone body metabolism is intact even initially after disease manifestation. One reason for the impaired glucose metabolism may be early destruction of the noradrenergic brain stem nucleus, locus coeruleus, which stimulates glucose metabolism, at least in astrocytes. These glial cells are essential in Alzheimer pathogenesis. The ß-amyloid peptide Aß interferes with their cholinergic innervation, which impairs synaptic function because of diminished astrocytic glutamate release. Aß also reduces glucose metabolism and causes hyperexcitability. Ketone bodies are similarly used against seizures, but the effectively used concentrations are so high that they must interfere with glucose metabolism and de novo synthesis of neurotransmitter glutamate, reducing neuronal glutamatergic signaling. The lower ketone body concentrations used in Alzheimer's disease may owe their effect to support of energy metabolism, but might also inhibit release of gliotransmitter glutamate. Alzheimer's disease is a panglial-neuronal disorder with long-standing brain hypometabolism, aberrations in both neuronal and astrocytic glucose metabolism, inflammation, hyperexcitability, and dementia. Relatively low doses of ß-hydroxybutyrate can have an ameliorating effect on cognitive function. This could be because of metabolic supplementation or inhibition of Aß-induced release of glutamate as gliotransmitter, which is likely to reduce hyperexcitability and inflammation. The therapeutic ß-hydroxybutyrate doses are too low to reduce neuronally released glutamate.

Novel insight into astrocyte-mediated gliotransmission modulates the synaptic plasticity in major depressive disorder.

Major depressive disorder (MDD) is a form of glial cell-based synaptic dysfunction disease in which glial cells interact closely with neuronal synapses and perform synaptic information processing. Glial cells, particularly astrocytes, are active components of the brain and are responsible for synaptic activity through the release gliotransmitters. A reduced density of astrocytes and astrocyte dysfunction have both been identified the brains of patients with MDD. Furthermore, gliotransmission, i.e., active information transfer mediated by gliotransmitters between astrocytes and neurons, is thought to be involved in the pathogenesis of MDD. However, the mechanism by which astrocyte-mediated gliotransmission contributes to depression remains unknown. This review therefore summarizes the alterations in astrocytes in MDD, including astrocyte marker, connexin 43 (Cx43) expression, Cx43 gap junctions, and Cx43 hemichannels, and describes the regulatory mechanisms of astrocytes involved in synaptic plasticity. Additionally, we investigate the mechanisms acting of the glutamatergic, gamma-aminobutyric acidergic, and purinergic systems that modulate synaptic function and the antidepressant mechanisms of the related receptor antagonists. Further, we summarize the roles of glutamate, gamma-aminobutyric acid, d-serine, and adenosine triphosphate in depression, providing a basis for the identification of diagnostic and therapeutic targets for MDD.

Inhibition of P2X4 and P2X7 receptors improves histological and behavioral outcomes after experimental traumatic brain injury in rats.

Release of large amounts of adenosine triphosphate (ATP), a gliotransmitter, into the extracellular space by traumatic brain injury (TBI) is considered to activate the microglia followed by release of inflammatory cytokines resulting in excessive inflammatory response that induces secondary brain injury. The present study investigated whether antagonists of ATP receptors (P2X4 and/or P2X7) on microglia are beneficial for reducing the post-injury inflammatory response that leads to secondary injury, a prognostic aggravation factor of TBI. Adult male Sprague-Dawley rats were subjected to cortical contusion injury (CCI) and randomly assigned to injury and drug treatment conditions, as follows: i) No surgical intervention (naïve group); ii) dimethyl sulfoxide treatment after CCI (CCI-control group); iii) 5-BDBD (antagonist of P2X4 receptor) treatment after CCI (CCI-5-BDBD group); iv) CCI-AZ11645373 (antagonist of P2X7 receptor) treatment after CCI (CCI-AZ11645373 group); v) or 5-BDBD and AZ11645373 treatment after CCI (CCI-5-BDBD + AZ11645373 group). In the CCI-5-BDBD, CCI-AZ11645373, and CCI-5-BDBD + AZ11645373 groups, expression of activated microglia was suppressed in the ipsilateral cortex and hippocampus 3 days after the CCI. Western blotting with ionized calcium-binding adaptor molecule 1 antibody revealed that administration of CCI-5-BDBD and/or CCI-AZ11645373 suppressed expression of microglia and reduced expression of inflammatory cytokine mRNA 3 days after the CCI. Furthermore, the plus maze test, which reflects the spatial memory function and involves the hippocampal function, showed improvement 28 days after secondary injury to the hippocampus. These findings confirmed that blocking the P2X4 and P2X7 receptors, which are ATP receptors central in gliotransmission, suppresses microglial activation and subsequent cytokine expression after brain injury, and demonstrates the potential as an effective treatment for reducing secondary brain injury.

Crosstalk of Astrocytes and Other Cells during Ischemic Stroke.

Stroke is a leading cause of death and long-term disability worldwide. Astrocytes structurally compose tripartite synapses, blood-brain barrier, and the neurovascular unit and perform multiple functions through cell-to-cell signaling of neurons, glial cells, and vasculature. The crosstalk of astrocytes and other cells is complicated and incompletely understood. Here we review the role of astrocytes in response to ischemic stroke, both beneficial and detrimental, from a cell-cell interaction perspective. Reactive astrocytes provide neuroprotection through antioxidation and antiexcitatory effects and metabolic support; they also contribute to neurorestoration involving neurogenesis, synaptogenesis, angiogenesis, and oligodendrogenesis by crosstalk with stem cells and cell lineage. In the meantime, reactive astrocytes also play a vital role in neuroinflammation and brain edema. Glial scar formation in the chronic phase hinders functional recovery. We further discuss astrocyte enriched microRNAs and exosomes in the regulation of ischemic stroke. In addition, the latest notion of reactive astrocyte subsets and astrocytic activity revealed by optogenetics is mentioned. This review discusses the current understanding of the intimate molecular conversation between astrocytes and other cells and outlines its potential implications after ischemic stroke. "Neurocentric" strategies may not be sufficient for neurological protection and recovery; future therapeutic strategies could target reactive astrocytes.