Role Of Astroglia Research Articles

APOE genotype and biological sex regulate astroglial interactions with amyloid plaques in Alzheimer’s disease mice

The most significant genetic risk factor for developing late-onset Alzheimer’s disease (AD) is the ε4 allele of apolipoprotein E (APOE4). APOE genotype and biological sex are key modulators of microglial and astroglial function, which exert multiple effects on AD pathogenesis. Here, we show astroglial interactions with amyloid plaques in the EFAD transgenic mouse model of AD. Using confocal microscopy, we observed significantly lower levels of astrocytic plaque coverage and plaque compaction (beneficial effects of glial barrier formation) with APOE4 genotype and female sex. Conversely, neurite damage and astrocyte activation in the plaque environment were significantly higher in APOE4 carriers and female mice. Astrocyte coverage of plaques was highest in APOE3 males and poorest in APOE4 females. Collectively, our findings provide new insights into the roles of astroglia and highlight the importance of addressing independent and interactive effects of APOE genotype and biological sex in understanding processes contributing to AD pathogenesis.

Astrocyte calcium dysfunction causes early network hyperactivity in Alzheimer's disease.

SummaryDysfunctions of network activity and functional connectivity (FC) represent early events in Alzheimer’s disease (AD), but the underlying mechanisms remain unclear. Astrocytes regulate local neuronal activity in the healthy brain, but their involvement in early network hyperactivity in AD is unknown. We show increased FC in the human cingulate cortex several years before amyloid deposition. We find the same early cingulate FC disruption and neuronal hyperactivity in AppNL-F mice. Crucially, these network disruptions are accompanied by decreased astrocyte calcium signaling. Recovery of astrocytic calcium activity normalizes neuronal hyperactivity and FC, as well as seizure susceptibility and day/night behavioral disruptions. In conclusion, we show that astrocytes mediate initial features of AD and drive clinically relevant phenotypes.

Astrocytes Derived from Familial and Sporadic Alzheimer's Disease iPSCs Show Altered Calcium Signaling and Respond Differently to Misfolded Protein Tau.

Astrocytes regulate important functions in the brain, and their dysregulation has been linked to the etiology of neurodegenerative diseases, such as Alzheimer’s disease (AD). The role of astroglia in human AD remains enigmatic, owing to the limitations of animal models, which, while recreating some pathological aspects of the disease, do not fully mirror its course. In addition, the recognition of major structural and functional differences between human and mouse astrocytes has also prompted research into human glial cells. In the current study, astrocytes were generated using human iPSCs from patients with sporadic Alzheimer’s disease (sAD), familial Alzheimer’s disease (fAD) and non-demented controls (NDC). All clones gained astrocyte-specific morphological and proteomic characteristics upon in vitro differentiation, without considerable inter-clonal variances. In comparison to NDC, AD astrocytes displayed aberrant calcium dynamics in response to glutamate. When exposed to monomeric and aggregated tau, AD astrocytes demonstrated hypertrophy and elevated GFAP expression, differential expression of select signaling and receptor proteins, and the enhanced production of metalloproteinases (MMPs). Moreover, astrocytic secretomes were able to degrade tau in both monomeric and pathologically aggregated forms, which was mediated by MMP-2 and -9. The capacity to neutralize tau varied considerably between clones, with fAD astrocytes having the lowest degradability relative to sAD and healthy astrocytes. Importantly, when compared to aggregated tau alone, astrocytic secretome pretreatment of tau differentially reduced its detrimental effects on neurons. Our results show crucial differences in sporadic and familial AD astrocytes and suggests that these cells may play distinctive roles in the pathogenesis of early and late onset Alzheimer’s disease.

A human iPSC-astroglia neurodevelopmental model reveals divergent transcriptomic patterns in schizophrenia

While neurodevelopmental abnormalities have been associated with schizophrenia (SCZ), the role of astroglia in disease pathophysiology remains poorly understood. In the present study, we used a human induced pluripotent stem cell (iPSC)-derived astrocyte model to investigate the temporal patterns of astroglia differentiation during developmental stages critical for SCZ using RNA sequencing. The model generated astrocyte-specific gene expression patterns during differentiation that corresponded well to astroglia-specific expression signatures of in vivo cortical fetal development. Using this model we identified SCZ-specific expression dynamics, and found that SCZ-associated differentially expressed genes were significantly enriched in the medial prefrontal cortex, striatum, and temporal lobe, targeting VWA5A and ADAMTS19. In addition, SCZ astrocytes displayed alterations in calcium signaling, and significantly decreased glutamate uptake and metalloproteinase activity relative to controls. These results implicate novel transcriptional dynamics in astrocyte differentiation in SCZ together with functional changes that are potentially important biological components of SCZ pathology.

From Physiology to Pathology of Cortico-Thalamo-Cortical Oscillations: Astroglia as a Target for Further Research.

The electrographic hallmark of childhood absence epilepsy (CAE) and other idiopathic forms of epilepsy are 2.5–4 Hz spike and wave discharges (SWDs) originating from abnormal electrical oscillations of the cortico-thalamo-cortical network. SWDs are generally associated with sudden and brief non-convulsive epileptic events mostly generating impairment of consciousness and correlating with attention and learning as well as cognitive deficits. To date, SWDs are known to arise from locally restricted imbalances of excitation and inhibition in the deep layers of the primary somatosensory cortex. SWDs propagate to the mostly GABAergic nucleus reticularis thalami (NRT) and the somatosensory thalamic nuclei that project back to the cortex, leading to the typical generalized spike and wave oscillations. Given their shared anatomical basis, SWDs have been originally considered the pathological transition of 11–16 Hz bursts of neural oscillatory activity (the so-called sleep spindles) occurring during Non-Rapid Eye Movement (NREM) sleep, but more recent research revealed fundamental functional differences between sleep spindles and SWDs, suggesting the latter could be more closely related to the slow (<1 Hz) oscillations alternating active (Up) and silent (Down) cortical activity and concomitantly occurring during NREM. Indeed, several lines of evidence support the fact that SWDs impair sleep architecture as well as sleep/wake cycles and sleep pressure, which, in turn, affect seizure circadian frequency and distribution. Given the accumulating evidence on the role of astroglia in the field of epilepsy in the modulation of excitation and inhibition in the brain as well as on the development of aberrant synchronous network activity, we aim at pointing at putative contributions of astrocytes to the physiology of slow-wave sleep and to the pathology of SWDs. Particularly, we will address the astroglial functions known to be involved in the control of network excitability and synchronicity and so far mainly addressed in the context of convulsive seizures, namely (i) interstitial fluid homeostasis, (ii) K+ clearance and neurotransmitter uptake from the extracellular space and the synaptic cleft, (iii) gap junction mechanical and functional coupling as well as hemichannel function, (iv) gliotransmission, (v) astroglial Ca2+ signaling and downstream effectors, (vi) reactive astrogliosis and cytokine release.

Morphological Features of Astrocytes in Health and Neuropsychiatric Disorders.

Astroglial cells actively partner with several cell types to regulate the arrangement of neuronal circuits both in the developing and adult brain. Morphological features of astroglial cells strongly impact their functional interactions, thereby supporting the hypothesis that aberrancies in glial morphology may trigger the onset of neuropsychiatric disorders. Thus, understanding the factors which modulate astroglial shapes and the development of tools to examine them may help to gain valuable insights about the role of astroglia in physiological and pathological brain states.Here, we present a collection of representative review and original articles describing the major morphological features which define different subtypes of glial cells and emphasize a high degree of heterogeneity typical of these cell types, besides neurons. Furthermore, we offer an overview about first in vitro and in vivo evidences, which highlight an altered morphology of glial cells in brains of psychiatric patients and animal models of neuropsychiatric disorders.

Molecularly defined cortical astroglia subpopulation modulates neurons via secretion of Norrin.

Despite expanding knowledge regarding the role of astroglia in regulating neuronal function, little is known about regional or functional subgroups of brain astroglia and how they may interact with neurons. We use an astroglia-specific promoter fragment in transgenic mice to identify an anatomically defined subset of adult grey matter astroglia. Using transcriptomic and histological analyses, we generate a combinatorial profile for in vivo identification and characterization of this astroglia subpopulation. These astroglia are enriched in cortical layer V, express distinct molecular markers, including norrin and LGR6, with corresponding layer-specific neuronal ligands, are found in human cortex and modulate neuronal activity. Astrocytic norrin appears to regulate dendrites and spines and its loss, as occurs in Norrie disease, contributes to cortical dendritic spine loss. These studies provide evidence that human and rodent astroglia subtypes are regionally and functionally distinct, can regulate local neuronal dendrite and synaptic spine development and contribute to disease.

Role of astroglia in diet-induced central neuroplasticity.

Obesity, characterized by increased adiposity that develops when energy intake outweighs expenditure, is rapidly becoming a serious health crisis that affects millions of people worldwide and is associated with severe comorbid disorders including hypertension, cardiovascular disease, and type II diabetes. Obesity is also associated with the dysregulation of central neurocircuits involved in the control of autonomic, metabolic, and cognitive functions. Systemic inflammation associated with diet-induced obesity (DIO) has been proposed to be responsible for the development of these comorbidities as well as the dysregulation of central neurocircuits. A growing body of evidence suggests, however, that exposure to a high-fat diet (HFD) may cause neuroinflammation and astroglial activation even before systemic inflammation develops, which may be sufficient to cause dysregulation of central neurocircuits involved in energy homeostasis before the development of obesity. The purpose of this review is to summarize the current literature exploring astroglial-dependent modulation of central circuits following exposure to HFD and DIO, including not only dysregulation of neurocircuits involved in energy homeostasis and feeding behavior, but also the dysregulation of learning, memory, mood, and reward pathways.

Pathoarchitectonics of the cerebral cortex in chorea-acanthocytosis and Huntington's disease.

Quantitative estimation of cortical neurone loss in cases with chorea-acanthocytosis (ChAc) and its impact on laminar composition. We used unbiased stereological tools to estimate the degree of cortical pathology in serial gallocyanin-stained brain sections through the complete hemispheres of three subjects with genetically verified ChAc and a range of disease durations. We compared these results with our previous data of five Huntington's disease (HD) and five control cases. Pathoarchitectonic changes were exemplarily documented in TE1 of a 61-year-old female HD-, a 60-year-old female control case, and ChAc3. Macroscopically, the cortical volume of our ChAc cases (ChAc1-3) remained close to normal. However, the average number of neurones was reduced by 46% in ChAc and by 33% in HD (P = 0.03 for ChAc & HD vs. controls; P = 0.64 for ChAc vs. HD). Terminal HD cases featured selective laminar neurone loss with pallor of layers III, V and VIa, a high density of small, pale, closely packed radial fibres in deep cortical layers VI and V, shrinkage, and chromophilia of subcortical white matter. In ChAc, pronounced diffuse astrogliosis blurred the laminar borders, thus masking the complete and partial loss of pyramidal cells in layer IIIc and of neurones in layers III, V and VI. ChAc is a neurodegenerative disease with distinct cortical neurodegeneration. The hypertrophy of the peripheral neuropil space of minicolumns with coarse vertical striation was characteristic of ChAc. The role of astroglia in the pathogenesis of this disorder remains to be elucidated.

Modern view on hepatic encephalopathy: basic terms and concepts of pathogenesis

Background. The problem of acute and chronic forms of hepatic encephalopathy (HE) is not clearly identified among modern problems of hepatology and neuroscience in Ukraine. Despite the significant contribution to the development of lethal complications in patients with liver pathology and long history of the study of this issue, there is still no unified opinion on the links of HE pathogenesis.The aim of this review is to conduct a comprehensive analysis of current data on the spreading and mechanisms of development of HE.HE is a complex of potentially reversible neurocognitive disorders in patients with chronic or acute hepatic failure (ALF). HE is more often a complication of liver cirrhosis and is the second most frequent cause of hospitalization of such patients after ascites. When decompensating liver failure in acute or chronic hepatic pathology in patients severe forms of HE develop, accompanied by a progressive increase in intracranial pressure and the development of coma, which often ends lethal due to poor corrigibility of intracranial hypertension while maintaining hepatogenic neurointoxication. HE is considered as the end result of the accumulation of a number of neurotoxic substances in the brain, among which are ammonia, mercaptans, short chain fatty acids, false neurotransmitters, gamma-aminobutyric acid, manganese. The most popular among the reasons for the development of HE is the neurotoxic theory of ammonia. Ammonia is subjected to detoxification in the liver, turning into urea, a smaller fraction with the participation of glutamine synthetase is used in the synthesis of glutamine in muscles, liver and astrocytes of brain. In case of hepatic dysfunction and/or portosystemic shunting, the concentration of ammonia in blood increases up to 10 times and the main load for its detoxification is shifted to myocytes and astroglia. In ALF glutamine overload of astrocytes occurs with a change in intracellular osmolarity and subsequent edema of astroglia, which is accompanied by the development of cytotoxic edema of the brain. In this case, in astrocytes damaging of mitochondrial respiratory chain occurs and mitochondrial insufficiency develops, as well as processes of nitrosative-oxidative stress and oxidation of astrocytic and neuronal RNA, disruption of gene expression, synthesis of neuro- and gliotransmitters and synaptic plasticity. The increased influx of aromatic amino acids into brain leads to the synthesis of false neurotransmitters, which worsens serotoninergic, GABA-ergic, dopaminergic and glutamatergic neurotransmission. Damage to the components of the blood-brain barrier leads to aggravation of the water imbalance, penetration of hematogenous cytokines, endotoxins and other products of systemic inflammatory reaction into the cerebral parenchyma and development of neuroinflammation, which makes an important contribution to the further progression of cerebral edema.Conclusions: despite a comprehensive study of the problem, many open questions remain in the pathogenesis of HE. Special attention should be paid to more detailed study of the mechanisms of formation and elimination of edematous changes in brain tissue on the background of hepatogenic intoxication and the development of a systemic inflammatory reaction, the role of astroglia and its water channels in these processes, as well as the mechanisms of damage to the blood-brain barrier.

A role for astroglia in prion diseases.

In this issue of JEM, Krejciova et al. (https://doi.org/10.1084/jem.20161547) report that astrocytes derived from human iPSCs can replicate human CJD prions. These observations provide a new, potentially very valuable model for studying human prions in cellula and for identifying antiprion compounds that might serve as clinical candidates. Furthermore, they add to the evidence that astrocytes may not be just innocent bystanders in prion diseases.

Neurotoxicity of Lead (PB) for Developing Brain. The Mechanisms of Action

Introduction: Long-term exposures to relatively low concentrations of lead (Pb) are usually asymptomatic and subclinical (microintoxication) and actually dominate among environmental intoxications in children, producing adverse health effects. The objectives relied on the assessment of pre-, neonatal exposure of rats to Pb with regard to: 1) parameters of the energy state of some structures of the brain; 2) pro- and antioxidant equilibrium and effectiveness of systems protecting neurons against Pb toxicity; 3) processes of apoptosis; 4) anatomy and ultrastructure of the hippocampus; 5) role of astroglia in neuroprotective and neurodegenerative processes of the developing brain. Methods: The study was done in Wistar rat pups pre- and neonatally exposed to 0.1% lead acetate (PbAc). PbAc was administered ad libitum to pregnant rats starting from the first day of pregnancy until birth and then during the lactation period. Pups were fed by the mothers until day 21 of life. Blood, cerebral cortex, cerebellum, and hippocampus were collected on day 29 of life for analysis. Results: Pb neurotoxicity during brain development 1) interferes with the energy state of the brain by depleting the ATP. The mechanisms are changes in the ultrastructure and function of mitochondria caused by Pb; 2) induces a disequilibrium between pro-and antioxidants manifested with reduced activities of antioxidative enzymes, available pool of antioxidant enzyme cofactors as well as with increased concentrations of reactive oxygen species; 3) stimulates the astrocyte pool; 4) does not mediate neurodegeneration expressed as apoptosis or necrosis; 5) elicits neurons and astrocytes response featuring neuroprotection through increased concentration of adenosine. Conclusion: Calls for a revision of the „safe concentration of Pb in blood” to a value below 10 μg/dL and for further investigations on the safe threshold of Pb during brain development.

The Role of Astroglia in the Antidepressant Action of Deep Brain Stimulation.

With more than 350 million depressed individuals worldwide, major depressive disorder is one of the most common psychiatric illnesses. Although, the pathophysiology of depression is far from being fully understood, five decades of development of different classes of antidepressants targeting central monoaminergic systems (serotonin, noradrenaline and dopamine) has led to the emergence of the monoaminergic hypothesis. However, despite a growing number of available pharmacotherapies, treatment of major depression nevertheless remains unsatisfactory.

Mutation of ataxia-telangiectasia mutated is associated with dysfunctional glutathione homeostasis in cerebellar astroglia.

Astroglial dysfunction plays an important role in neurodegenerative diseases otherwise attributed to neuronal loss of function. Here we focus on the role of astroglia in ataxia-telangiectasia (A-T), a disease caused by mutations in the ataxia-telangiectasia mutated (ATM) gene. A hallmark of A-T pathology is progressive loss of cerebellar neurons, but the mechanisms that impact neuronal survival are unclear. We now provide a possible mechanism by which A-T astroglia affect the survival of cerebellar neurons. As astroglial functions are difficult to study in an in vivo setting, particularly in the cerebellum where these cells are intertwined with the far more numerous neurons, we conducted in vitro coculture experiments that allow for the generation and pharmacological manipulation of purified cell populations. Our analyses revealed that cerebellar astroglia isolated from Atm mutant mice show decreased expression of the cystine/glutamate exchanger subunit xCT, glutathione (GSH) reductase, and glutathione-S-transferase. We also found decreased levels of intercellular and secreted GSH in A-T astroglia. Metabolic labeling of l-cystine, the major precursor for GSH, revealed that a key component of the defect in A-T astroglia is an impaired ability to import this rate-limiting precursor for the production of GSH. This impairment resulted in suboptimal extracellular GSH supply, which in turn impaired survival of cerebellar neurons. We show that by circumventing the xCT-dependent import of L-cystine through addition of N-acetyl-L-cysteine (NAC) as an alternative cysteine source, we were able to restore GSH levels in A-T mutant astroglia providing a possible future avenue for targeted therapeutic intervention.

Role of astroglia in Down’s syndrome revealed by patient-derived human-induced pluripotent stem cells

Down’s syndrome (DS), caused by trisomy of human chromosome 21, is the most common genetic cause of intellectual disability. Here we use induced pluripotent stem cells (iPSCs) derived from DS patients to identify a role for astrocytes in DS pathogenesis. DS astroglia exhibit higher levels of reactive oxygen species and lower levels of synaptogenic molecules. Astrocyte-conditioned medium collected from DS astroglia causes toxicity to neurons, and fails to promote neuronal ion channel maturation and synapse formation. Transplantation studies show that DS astroglia do not promote neurogenesis of endogenous neural stem cells in vivo. We also observed abnormal gene expression profiles from DS astroglia. Finally, we show that the FDA-approved antibiotic drug, minocycline, partially corrects the pathological phenotypes of DS astroglia by specifically modulating the expression of S100B, GFAP, inducible nitric oxide synthase, and thrombospondins 1 and 2 in DS astroglia. Our studies shed light on the pathogenesis and possible treatment of DS by targeting astrocytes with a clinically available drug.

Roles of astroglia in the regulations of brain vascular permeability

くも膜下出血や脳血栓などの脳卒中の急性期には，脳浮腫が生じる．脳浮腫は致死的な病態であるが，効果的な薬物治療は開発されていない．脳浮腫の発生にはアストログリアの産生する血管透過性亢進因子が関わる．そのため，脳損傷時のアストログリアの機能をコントロールし浮腫の発生を抑制しようとする創薬ストラテジーが提唱されている．我々はこのストラテジーの有効性を，アストログリアに高く発現しているエンドセリン（ET）受容体を，薬物標的として検討した．マウス大脳の凍結傷害は，損傷部位での血液脳関門の破綻と脳組織水分含量の増加（脳浮腫）を引き起こした．凍結傷害により惹起された脳浮腫は，傷害前でのETB アンタゴニストBQ788 の投与により抑制された．また，BQ788 の傷害前投与は，血中タンパク質のマーカーであるEvans blueおよび内因性アルブミンの漏出を抑制した．一方，凍結傷害による浮腫が形成された後での投与でも，BQ788 は脳浮腫および血中タンパク質の漏出を抑制した．ラット大脳および培養アストログリアでのETB 受容体の刺激は，血管透過性亢進因子であるMMP9 およびVEGF-A の発現を増加させた．また，アストログリアのAQP4 は脳内に蓄積した水の排出経路として働くが，ラット脳および培養アストログリアでのAQP4 発現は，ETB アゴニストにより減少した．凍結傷害は，マウス大脳でのMMP9 およびVEGF-A の発現を増加させたが，これらの増加はBQ788 投与により減少した．また，凍結傷害によるAQP4 発現減少も，BQ788 投与により抑制された．以上の結果は，脳損傷による浮腫発生へのET の関与を示すと共に，ETB 受容体が脳浮腫治療薬の標的分子となり得ることを示唆する．

Involvement of spinal chemokine CCL2 in the hyperalgesia evoked by bone cancer in mice: a role for astroglia and microglia.

The hypernociceptive role played by the chemokine CCL2, and its main receptor, CCR2, in pathological settings is being increasingly recognized. We aimed to characterize the involvement of spinal CCL2 in the hyperalgesia due to the intratibial inoculation of fibrosarcoma NCTC 2472 cells in mice. The intrathecal (i.t.) administration of the CCR2 antagonist RS 504393 (1–3 μg) or an anti-CCL2 antibody inhibited tumoral hyperalgesia. No change in the expression of spinal CCR2 was detected by western blot, whereas immunohistochemical experiments demonstrated increased CCL2 staining at the superficial laminae of the spinal cord ipsilateral to the tumor. This spinal CCL2 does not seem to be released from nociceptors since CCL2 mRNA and CCL2 levels in DRGs, as measured by RT-PCR and ELISA, remain unmodified in tumor-bearing mice. In contrast, immunohistochemical assays demonstrated the spinal up-regulations of GFAP and Iba-1, respective markers of astroglia and microglia, and the expression of CCL2 in both types of glial cells at the superficial laminae of the spinal cord of tumor-bearing mice. Finally, since CCL2 could induce astroglial or microglial activation, we studied whether the blockade of CCR2 could inhibit the increased spinal glial expression. GFAP, but not Iba-1, up-regulation was reduced in tumor-bearing mice treated for 3 days with i.t. RS 504393, indicating that spinal CCL2 acts as an astroglial activator in this setting. The participation at spinal level of CCL2/CCR2 in tumoral hypernociception, together with its previously described involvement at periphery, makes attractive the modulation of this system for the alleviation of neoplastic pain.

All astrocytes are not created equal--the role of astroglia in brain injury.

In two recent papers published in Nature Neuroscience and Cell Stem Cells, Magdalena Götz and colleagues shed new light on the in vivo response of glial cells to brain injury and characterize a highly heterogeneous behavior of astrocytes to chronic and acute brain injury.

Mechanisms underlying blood–brain barrier dysfunction in brain pathology and epileptogenesis: Role of astroglia

Astrocytes are increasingly recognized as equal partners to neurons, also contributing to neurologic disorders such as epilepsy. Activated astrocytes are a common hallmark in patients with mesial temporal lobe epilepsy and Ammon's horn sclerosis. Blood-brain barrier (BBB) opening during status epilepticus has short-term proepileptic effects, as the ionic composition of serum interferes with neuronal excitability. In the long run, astrocytic uptake of albumin induces transforming growth factor β (TGFβ)-mediated signaling cascades, leading to changes in astrocytic properties. Down-regulation of astrocytic inward rectifier K(+) channels and altered surface expression of the water channel, aquaporin 4 results in disturbances in spatial K(+) buffering, thereby rendering the tissue more seizure prone. The expression of astrocytic gap junctional proteins connexin 43 (Cx43) and connexin 30 (Cx30) is altered in epilepsy, and changes in gap junctional communication were found in sclerotic hippocampal tissue in animal models of epilepsy. Although gap junctional communication might exert both proepileptic and antiepileptic effects, double knock out of Cx43 and Cx30 resulted in occurrence of spontaneous epileptiform events. Seizures are associated with massive increases in cerebral blood flow in order to cover the increased energy demand. Hemodynamic responses at the microcirculation level are mediated by astrocyte-pericyte interactions, sharing common mechanisms with spatial K(+) buffering. Although many of the astrocytic mechanisms involving spatial K(+) buffering, nitric oxide, adenosine, and metabotropic glutamate receptor (mGluR)-mediated signalling are altered in epilepsy, little is known how these alterations affect neurovascular coupling. In conclusion, astrocytic activation preceding alterations in neuronal function might critically contribute to epileptogenesis. Therefore, astrocytes represent a promising new target for the development of antiepileptic drugs.

New role for astroglia in learning: Formation of muscle memory

Muscle memory can be described as gradual adaptation of muscles over a period of time to perform a new movement or action. Its precise mechanism is unknown; however, it is now known that when a motor skill is learned it leads to significant brain activity. Astrocytes are the most abundant glial cell types in the CNS that play an associative active role with neurons in learning and memory. They are interconnected to neurons via gap junctions forming astroglial network for fast communication and synchronization. We hypothesize that astroglial cells play main role in the formation of muscle memory and evaluate it by the experimental evidence published so far that indicates role of astroglia on various cellular and molecular aspects of muscle memory. The basis of our hypothesis is the fact that during training or motor learning period, neuronal output data related to learning lead to certain specific pattern for stimulating target muscles over a period of time and partly these data are stored in astroglial network. This stored data fine tune glial parameters that affect synaptic space and neuronal output used to perform rapid motor actions. For the validation of our hypothesis, we have generated a computational model for a section of neural pathway with astroglial network and have shown that the astroglial network by using inhibitory and stimulatory neurotransmitters can generate certain patterns, modulate and balance synaptic space across the neural pathway during acquisition of muscle memory.