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Astrocyte
Astrocyte
Astrocyte
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Astrocyte
An astrocyte from a rat brain grown in tissue culture and stained with antibodies to GFAP (red) and vimentin (green). Both proteins are present in large amounts in the intermediate filaments of this cell, so the cell appears yellow. The blue material shows DNA visualized with DAPI stain, and reveals the nucleus of the astrocyte and of other cells. Image courtesy of EnCor Biotechnology Inc.
Details
PrecursorGlioblast
LocationBrain and spinal cord
Identifiers
Latinastrocytus
MeSHD001253
NeuroLex IDsao1394521419
THH2.00.06.2.00002, H2.00.06.2.01008
FMA54537
Anatomical terms of microanatomy

Astrocytes (from Ancient Greek ἄστρον, ástron, "star" and κύτος, kútos, "cavity", "cell"), also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord. They perform many functions, including biochemical control of endothelial cells that form the blood–brain barrier,[1] provision of nutrients to the nervous tissue, maintenance of extracellular ion balance, regulation of cerebral blood flow, and a role in the repair and scarring process of the brain and spinal cord following infection and traumatic injuries.[2] The proportion of astrocytes in the brain is not well defined; depending on the counting technique used, studies have found that the astrocyte proportion varies by region and ranges from 20% to around 40% of all glia.[3] Another study reports that astrocytes are the most numerous cell type in the brain.[2] Astrocytes are the major source of cholesterol in the central nervous system.[4] Apolipoprotein E transports cholesterol from astrocytes to neurons and other glial cells, regulating cell signaling in the brain.[4] Astrocytes in humans are more than twenty times larger than in rodent brains, and make contact with more than ten times the number of synapses.[5]

Research since the mid-1990s has shown that astrocytes propagate intercellular Ca2+ waves over long distances in response to stimulation, and, similar to neurons, release transmitters (called gliotransmitters) in a Ca2+-dependent manner.[6] Data suggest that astrocytes also signal to neurons through Ca2+-dependent release of glutamate.[7] Such discoveries have made astrocytes an important area of research within the field of neuroscience.

Structure

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Astrocytes (green) in the context of neurons (red) in a mouse cortex cell culture
23-week-old fetal brain culture human astrocyte
Astrocytes (red-yellow) among neurons (green) in the living cerebral cortex

Astrocytes are a sub-type of glial cells in the central nervous system. They are also known as astrocytic glial cells. Star-shaped, their many processes envelop synapses made by neurons. In humans, a single astrocyte cell can interact with up to 2 million synapses at a time.[8] Astrocytes are classically identified using histological analysis; many of these cells express the intermediate filament glial fibrillary acidic protein (GFAP).[9]

Types

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Several forms of astrocytes exist in the central nervous system: including fibrous (in white matter), protoplasmic (in grey matter), and radial.

Fibrous glia

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The fibrous glia are usually located within white matter, have relatively few organelles, and exhibit long unbranched cellular processes. This type often has astrocytic endfeet processes that physically connect the cells to the outside of capillary walls when they are in proximity to them.[10]

Protoplasmic glia

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The protoplasmic glia are the most prevalent and are found in grey matter tissue, possess a larger quantity of organelles, and exhibit short and highly branched tertiary processes.[citation needed]

Radial glia

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The radial glial cells are disposed in planes perpendicular to the axes of ventricles. One of their processes abuts the pia mater, while the other is deeply buried in gray matter. Radial glia are mostly present during development, playing a role in neuron migration. Müller cells of the retina and Bergmann glia cells of the cerebellar cortex represent an exception, being present still during adulthood. When in proximity to the pia mater, all three forms of astrocytes send out processes to form the pia-glial membrane.

Energy use

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Early assessments of energy use in gray matter signaling suggested that 95% was attributed to neurons and 5% to astrocytes.[11] However, after discovering that action potentials were more efficient than initially believed, the energy budget was adjusted: 70% for dendrites, 15% for axons, and 7% for astrocytes.[12] Previous accounts assumed that astrocytes captured synaptic K⁺ solely via Kir4.1 channels. However, it's now understood they also utilize Na⁺/K⁺ ATPase. Factoring in this active buffering, astrocytic energy demand increases by >200%. This is supported by 3D neuropil reconstructions indicating similar mitochondrial densities in both cell types, as well as cell-specific transcriptomic and proteomic data, and tricarboxylic acid cycle rates.[13] Therefore "Gram-per-gram, astrocytes turn out to be as expensive as neurons".[13]

Development

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Astrocytes are depicted in red. Cell nuclei are depicted in blue. Astrocytes were obtained from brains of newborn mice.

Astrocytes are macroglial cells in the central nervous system. Astrocytes are derived from heterogeneous populations of progenitor cells in the neuroepithelium of the developing central nervous system. There is remarkable similarity between the well known genetic mechanisms that specify the lineage of diverse neuron subtypes and that of macroglial cells.[14] Just as with neuronal cell specification, canonical signaling factors like sonic hedgehog (SHH), fibroblast growth factor (FGFs), WNTs and bone morphogenetic proteins (BMPs), provide positional information to developing macroglial cells through morphogen gradients along the dorsal–ventral, anterior–posterior and medial–lateral axes. The resultant patterning along the neuraxis leads to segmentation of the neuroepithelium into progenitor domains (p0, p1 p2, p3 and pMN) for distinct neuron types in the developing spinal cord. On the basis of several studies it is now believed that this model also applies to macroglial cell specification. Studies carried out by Hochstim and colleagues have demonstrated that three distinct populations of astrocytes arise from the p1, p2 and p3 domains.[15] These subtypes of astrocytes can be identified on the basis of their expression of different transcription factors (PAX6, NKX6.1) and cell surface markers (reelin and SLIT1). The three populations of astrocyte subtypes which have been identified are: 1) dorsally located VA1 astrocytes, derived from p1 domain, express PAX6 and reelin; 2) ventrally located VA3 astrocytes, derived from p3, express NKX6.1 and SLIT1; and 3) intermediate white-matter located VA2 astrocyte, derived from the p2 domain, which express PAX6, NKX6.1, reelin and SLIT1.[16] After astrocyte specification has occurred in the developing CNS, it is believed that astrocyte precursors migrate to their final positions within the nervous system before the process of terminal differentiation occurs.

Function

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Metabolic interactions between astrocytes and neurons[17]

Astrocytes help form the physical structure of the brain, and are thought to play a number of active roles, including the secretion or absorption of neural transmitters and maintenance of the blood–brain barrier.[18] The concept of a tripartite synapse has been proposed, referring to the tight relationship occurring at synapses among a presynaptic element, a postsynaptic element, and a glial element.[19]

Astrocyte endfeet processes surrounding a blood vessel
  • Structural: They are involved in the physical structuring of the brain. Astrocytes get their name because they are star-shaped. They are the most abundant glial cells in the brain that are closely associated with neuronal synapses. They regulate the transmission of electrical impulses within the brain.
  • Glycogen fuel reserve buffer: Astrocytes contain glycogen and are capable of gluconeogenesis. The astrocytes next to neurons in the frontal cortex and hippocampus store and release glucose. Thus, astrocytes can fuel neurons with glucose during periods of high rate of glucose consumption and glucose shortage. A recent research on rats suggests there may be a connection between this activity and physical exercise.[20]
  • Metabolic support: They provide neurons with nutrients such as lactate.
  • Glucose sensing: normally associated with neurons, the detection of interstitial glucose levels within the brain is also controlled by astrocytes. Astrocytes in vitro become activated by low glucose and are in vivo this activation increases gastric emptying to increase digestion.[21]
  • Blood–brain barrier: The astrocyte endfeet processes encircling endothelial cells were thought to aid in the maintenance of the blood–brain barrier, and recent research indicates that they do play a substantial role, along with the tight junctions and basal lamina.[citation needed] However, it has recently been shown that astrocyte activity is linked to blood flow in the brain, and that this is what is actually being measured in fMRI.[22][23]
  • Transmitter uptake and release: Astrocytes express plasma membrane transporters for several neurotransmitters, including glutamate, ATP, and GABA. More recently, astrocytes were shown to release glutamate or ATP in a vesicular, Ca2+-dependent manner.[24] (This has been disputed for hippocampal astrocytes.)[25]
  • Regulation of ion concentration in the extracellular space: Astrocytes express potassium channels at a high density. When neurons are active, they release potassium, increasing the local extracellular concentration. Because astrocytes are highly permeable to potassium, they rapidly clear the excess accumulation in the extracellular space.[26] If this function is interfered with, the extracellular concentration of potassium will rise, leading to neuronal depolarization by the Goldman equation. Abnormal accumulation of extracellular potassium is well known to result in epileptic neuronal activity.[27]
  • Modulation of synaptic transmission: In the supraoptic nucleus of the hypothalamus, rapid changes in astrocyte morphology have been shown to affect heterosynaptic transmission between neurons.[28] In the hippocampus, astrocytes suppress synaptic transmission by releasing ATP, which is hydrolyzed by ectonucleotidases to yield adenosine. Adenosine acts on neuronal adenosine receptors to inhibit synaptic transmission, thereby increasing the dynamic range available for LTP.[29]
  • Vasomodulation: Astrocytes may serve as intermediaries in neuronal regulation of blood flow.[30]
  • Promotion of the myelinating activity of oligodendrocytes: Electrical activity in neurons causes them to release ATP, which serves as an important stimulus for myelin to form. However, the ATP does not act directly on oligodendrocytes. Instead, it causes astrocytes to secrete cytokine leukemia inhibitory factor (LIF), a regulatory protein that promotes the myelinating activity of oligodendrocytes. This suggests that astrocytes have an executive-coordinating role in the brain.[31]
  • Nervous system repair: Upon injury to nerve cells within the central nervous system, astrocytes fill up the space to form a glial scar, and may contribute to neural repair. The role of astrocytes in CNS regeneration following injury is not well understood though. The glial scar has traditionally been described as an impermeable barrier to regeneration, thus implicating a negative role in axon regeneration. However, recently, it was found through genetic ablation studies that astrocytes are actually required for regeneration to occur.[32] More importantly, the authors found that the astrocyte scar is actually essential for stimulated axons (that axons that have been coaxed to grow via neurotrophic supplementation) to extend through the injured spinal cord.[32] Astrocytes that have been pushed into a reactive phenotype (termed astrogliosis, defined by the upregulation of among others, GFAP and vimentin[33] expression, a definition still under debate) may actually be toxic to neurons, releasing signals that can kill neurons.[34] Much work, however, remains to elucidate their role in nervous system injury.
  • Long-term potentiation: There is debate among scientists as to whether astrocytes integrate learning and memory in the hippocampus. Recently, it has been shown that engrafting human glial progenitor cell in nascent mice brains causes the cells to differentiate into astrocytes. After differentiation, these cells increase LTP and improve memory performance in the mice.[35]
  • Circadian clock: Astrocytes alone are sufficient to drive the molecular oscillations in the SCN and circadian behavior in mice, and thus can autonomously initiate and sustain complex mammalian behavior.[36]
  • The switch of the nervous system: Based on the evidence listed below, it has been recently conjectured in,[37] that macro glia (and astrocytes in particular) act both as a lossy neurotransmitter capacitor and as the logical switch of the nervous system. I.e., macroglia either block or enable the propagation of the stimulus along the nervous system, depending on their membrane state and the level of the stimulus.
Fig. 6 The conjectured switching role of glia in the biological neural detection scheme as suggested by Nossenson et al.[37][38]
Evidence supporting the switch and lossy capacitor role of glia as suggested in[37][38]
Evidence type Description References
Calcium evidence Calcium waves appear only if a certain concentration of neurotransmitter is exceeded [39][40][41]
Electrophysiological evidence A negative wave appears when the stimulus level crosses a certain threshold. The shape of the electrophysiological response is different and has the opposite polarity compared to the characteristic neural response, suggesting that cells other than neurons might be involved. [42][43]

[44] [45]

Psychophysical evidence The negative electrophysiological response is accompanied with all-or-none actions. A moderate negative electrophysiological response appears in conscious logical decisions such as perception tasks. An intense sharp negative wave appear in epileptic seizures and during reflexes. [42][45][43][44]
Radioactivity based glutamate uptake tests Glutamate uptake tests indicate that astrocyte process glutamate in a rate which is initially proportional to glutamate concentration. This supports the leaky capacitor model, where the 'leak' is glutamate processing by glia's glutamine synthetase. Furthermore, the same tests indicate on a saturation level after which neurotransmitter uptake level stops rising proportionally to neurotransmitter concentration. The latter supports the existence of a threshold. The graphs which show these characteristics are referred to as Michaelis-Menten graphs [46]

Astrocytes are linked by gap junctions, creating an electrically coupled (functional) syncytium.[47] Because of this ability of astrocytes to communicate with their neighbors, changes in the activity of one astrocyte can have repercussions on the activities of others that are quite distant from the original astrocyte.

An influx of Ca2+ ions into astrocytes is the essential change that ultimately generates calcium waves. Because this influx is directly caused by an increase in blood flow to the brain, calcium waves are said to be a kind of hemodynamic response function. An increase in intracellular calcium concentration can propagate outwards through this functional syncytium. Mechanisms of calcium wave propagation include diffusion of calcium ions and IP3 through gap junctions and extracellular ATP signalling.[48] Calcium elevations are the primary known axis of activation in astrocytes, and are necessary and sufficient for some types of astrocytic glutamate release.[49] Given the importance of calcium signaling in astrocytes, tight regulatory mechanisms for the progression of the spatio-temporal calcium signaling have been developed. Via mathematical analysis it has been shown that localized inflow of Ca2+ ions yields a localized raise in the cytosolic concentration of Ca2+ ions.[50] Moreover, cytosolic Ca2+ accumulation is independent of every intracellular calcium flux and depends on the Ca2+ exchange across the membrane, cytosolic calcium diffusion, geometry of the cell, extracellular calcium perturbation, and initial concentrations.[50]

Tripartite synapse

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Main article: Tripartite synapse

Within the dorsal horn of the spinal cord, activated astrocytes have the ability to respond to almost all neurotransmitters[51] and, upon activation, release a multitude of neuroactive molecules such as glutamate, ATP, nitric oxide (NO), and prostaglandins (PG), which in turn influences neuronal excitability. The close association between astrocytes and presynaptic and postsynaptic terminals as well as their ability to integrate synaptic activity and release neuromodulators has been termed the tripartite synapse.[19] Synaptic modulation by astrocytes takes place because of this three-part association.

A 2023 study suggested astrocytes, previously underexplored brain cells, could be key to extending wakefulness without negative effects on cognition and health.[52]

Glutamatergic gliotransmission

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Some specialized astrocytes mediate glutamatergic gliotransmission in the central nervous system.[53] Such cells have been called hybrid brain cells because they exhibit both neuron-like and glial-like properties. Unlike traditional neurons, these cells not only transmit electrical signals but also provide supportive roles typically associated with glial cells, such as regulating the brain's extracellular environment and maintaining overall homeostasis.[54][55][56]

Clinical significance

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Astrocytomas

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Astrocytomas are primary tumors in the CNS that develop from astrocytes. It is also possible that glial progenitors or neural stem cells can give rise to astrocytomas. These tumors may occur in many parts of the brain or spinal cord. Astrocytomas are divided into two categories: low grade (I and II) and high grade (III and IV). Low grade tumors are more common in children, and high grade tumors are more common in adults. Malignant astrocytomas are more prevalent among men, contributing to worse survival.[57]

Pilocytic astrocytomas are grade I tumors. They are considered benign and slow growing tumors. Pilocytic astrocytomas frequently have cystic portions filled with fluid and a nodule, which is the solid portion. Most are located in the cerebellum. Therefore, most symptoms are related to balance or coordination difficulties.[57] They also occur more frequently in children and teens.[58]

Fibrillary astrocytomas are grade II tumors. They grow relatively slowly so are usually considered benign, but they infiltrate the surrounding healthy tissue and can become malignant. Fibrillary astrocytomas commonly occur in younger people, who often present with seizures.[58]

Anaplastic astrocytomas are grade III malignant tumors. They grow more rapidly than lower grade tumors. Anaplastic astrocytomas recur more frequently than lower grade tumors because their tendency to spread into surrounding tissue makes them difficult to completely remove surgically.[57]

Glioblastoma is a grade IV cancer that may originate from astrocytes or an existing astrocytoma. Approximately 50% of all brain tumors are glioblastomas. Glioblastomas can contain multiple glial cell types, including astrocytes and oligodendrocytes. Glioblastomas are generally considered to be the most invasive type of glial tumor, as they grow rapidly and spread to nearby tissue. Treatment may be complicated, because one tumor cell type may die off in response to a particular treatment while the other cell types may continue to multiply.[57]

Neurodevelopmental disorders

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Astrocytes have emerged as important participants in various neurodevelopmental disorders. This view states that astrocyte dysfunction may result in improper neural circuitry, which underlies certain psychiatric disorders such as autism spectrum disorders and schizophrenia.[59][5]

Chronic pain

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Under normal conditions, pain conduction begins with some noxious signal followed by an action potential carried by nociceptive (pain sensing) afferent neurons, which elicit excitatory postsynaptic potentials (EPSP) in the dorsal horn of the spinal cord. That message is then relayed to the cerebral cortex, where we translate those EPSPs into "pain". Since the discovery of astrocyte-neuron signaling, our understanding of the conduction of pain has been dramatically complicated. Pain processing is no longer seen as a repetitive relay of signals from body to brain, but as a complex system that can be up- and down-regulated by a number of different factors. One factor at the forefront of recent research is in the pain-potentiating synapse located in the dorsal horn of the spinal cord and the role of astrocytes in encapsulating these synapses. Garrison and co-workers[60] were the first to suggest association when they found a correlation between astrocyte hypertrophy in the dorsal horn of the spinal cord and hypersensitivity to pain after peripheral nerve injury, typically considered an indicator of glial activation after injury. Astrocytes detect neuronal activity and can release chemical transmitters, which in turn control synaptic activity.[51][61][62] In the past, hyperalgesia was thought to be modulated by the release of substance P and excitatory amino acids (EAA), such as glutamate, from the presynaptic afferent nerve terminals in the spinal cord dorsal horn. Subsequent activation of AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid), NMDA (N-methyl-D-aspartate) and kainate subtypes of ionotropic glutamate receptors follows. It is the activation of these receptors that potentiates the pain signal up the spinal cord. This idea, although true, is an oversimplification of pain transduction. A litany of other neurotransmitter and neuromodulators, such as calcitonin gene-related peptide (CGRP), adenosine triphosphate (ATP), brain-derived neurotrophic factor (BDNF), somatostatin, vasoactive intestinal peptide (VIP), galanin, and vasopressin are all synthesized and released in response to noxious stimuli. In addition to each of these regulatory factors, several other interactions between pain-transmitting neurons and other neurons in the dorsal horn have added impact on pain pathways.

Two states of persistent pain

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After persistent peripheral tissue damage there is a release of several factors from the injured tissue as well as in the spinal dorsal horn. These factors increase the responsiveness of the dorsal horn pain-projection neurons to ensuing stimuli, termed "spinal sensitization", thus amplifying the pain impulse to the brain. Release of glutamate, substance P, and calcitonin gene-related peptide (CGRP) mediates NMDAR activation (originally silent because it is plugged by Mg2+), thus aiding in depolarization of the postsynaptic pain-transmitting neurons (PTN). In addition, activation of IP3 signaling and MAPKs (mitogen-activated protein kinases) such as ERK and JNK, bring about an increase in the synthesis of inflammatory factors that alter glutamate transporter function. ERK also further activates AMPARs and NMDARs in neurons. Nociception is further sensitized by the association of ATP and substance P with their respective receptors (P2X3) and neurokinin 1 receptor (NK1R), as well as activation of metabotropic glutamate receptors and release of BDNF. Persistent presence of glutamate in the synapse eventually results in dysregulation of GLT1 and GLAST, crucial transporters of glutamate into astrocytes. Ongoing excitation can also induce ERK and JNK activation, resulting in release of several inflammatory factors.

As noxious pain is sustained, spinal sensitization creates transcriptional changes in the neurons of the dorsal horn that lead to altered function for extended periods. Mobilization of Ca2+ from internal stores results from persistent synaptic activity and leads to the release of glutamate, ATP, tumor necrosis factor-α (TNF-α), interleukin 1β (IL-1β), IL-6, nitric oxide (NO), and prostaglandin E2 (PGE2). Activated astrocytes are also a source of matrix metalloproteinase 2 (MMP2), which induces pro-IL-1β cleavage and sustains astrocyte activation. In this chronic signaling pathway, p38 is activated as a result of IL-1β signaling, and there is a presence of chemokines that trigger their receptors to become active. In response to nerve damage, heat shock proteins (HSP) are released and can bind to their respective TLRs, leading to further activation.

Other pathologies

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See also: Neuroimmune system

Other clinically significant pathologies involving astrocytes include astrogliosis and astrocytopathy. Examples of these include multiple sclerosis, anti-AQP4+ neuromyelitis optica, Rasmussen's encephalitis, Alexander disease, and amyotrophic lateral sclerosis.[63] Studies have shown that astrocytes may be implied in neurodegenerative diseases, such as Alzheimer's disease,[64][65] Parkinson's disease,[66] Huntington's disease, Stuttering[67] and amyotrophic lateral sclerosis,[68] and in acute brain injuries, such as intracerebral hemorrhage [69] and traumatic brain injury.[70]

Gomori-positive astrocytes and brain dysfunction

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A type of astrocyte with an aging-related pathology has been described over the last fifty years. Astrocytes of this subtype possess prominent cytoplasmic granules that are intensely stained by Gomori's chrome alum hematoxylin stain, and hence are termed Gomori-positive (GP) astrocytes. They can be found throughout the brain, but are by far the most abundant in the olfactory bulbs, medial habenula, dentate gyrus of the hippocampus, arcuate nucleus of the hypothalamus, and in the dorsal medulla, just beneath the area postrema.[71]

Gomori-positive cytoplasmic granules are derived from damaged mitochondria engulfed within lysosomes.[72] Cytoplasmic granules contain undigested remnants of mitochondrial structures. These contents include heme-linked copper and iron atoms remaining from mitochondrial enzymes.[73] These chemical substances account for the pseudoperoxidase activity of Gomori-positive granules that can utilized to stain for these granules. Oxidative stress is believed to be cause of damage to these astrocytes.[74] However, the exact nature of this stress is uncertain.

Brain regions enriched in Gomori-positive astrocytes also contain a sub-population of specialized astrocytes that synthesize Fatty Acid Binding Protein 7 (FABP7). Indeed, astrocytes in the hypothalamus that synthesize FABP7 have also been shown to possess Gomori-positive granules.[75] Thus, a connection between these two glial features is apparent. Recent data have shown that astrocytes, but not neurons, possess the mitochondrial enzymes needed to metabolize fatty acids, and that the resulting oxidative stress can damage mitochondria.[76] Thus, an increased uptake and oxidation of fatty acids in glia containing FABP7 is likely to cause the oxidative stress and damage to mitochondria in these cells. Also, FABP proteins have recently been shown to interact with a protein called synuclein to cause mitochondrial damage.[77]

Possible roles in pathophysiology

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Astrocytes can transfer mitochondria into adjacent neurons to improve neuronal function.[78] It is therefore plausible that the damage to astrocyte mitochondria seen in GP astrocytes could affect the activity of neurons.

A number of hypothalamic functions show declines in aging that may be related to GP astrocytes. For example, GP astrocytes are in close contact with neurons that make a neurotransmitter called dopamine in both the rat and human hypothalamus.[79] The dopamine produced by these neurons is carried to the nearby pituitary gland to inhibit the release of a hormone called prolactin from the pituitary. The activity of dopaminergic neurons declines during aging, leading to elevations in blood levels of prolactin that can provoke breast cancer.[80] An aging-associated change in astrocyte function might contribute to this change in dopaminergic activity.

FABP7+ astrocytes are in close contact with neurons in the arcuate nucleus of the hypothalamus that are responsive to a hormone called leptin that is produced by fat cells. Leptin-sensitive neurons regulate appetite and body weight. FABP7+ astrocytes regulate the responsiveness of these neurons to leptin. Mitochondrial damage in these astrocytes could thus alter the function of leptin-sensitive neurons and could contribute to an aging-associated dysregulation of feeding and body weight.[81]

GP astrocytes may also be involved in the hypothalamic regulation of overall glucose metabolism. Recent data show that astrocytes function as glucose sensors and exert a commanding influence upon neuronal reactivity to changes in extracellular glucose.[82] GP astrocytes possess high-capacity GLUT2-type glucose transporter proteins and appear to modulate the neuronal responses to glucose.[83] Hypothalamic cells monitor blood levels of glucose and exert an influence upon blood glucose levels via an altered input to autonomic circuits that innervate liver and muscle cells.

The importance of astrocytes in aging-related disturbances in glucose metabolism has been recently illustrated by studies of diabetic animals. A single infusion of a protein called fibroblast growth factor-1 into the hypothalamus has been shown to permanently normalize blood glucose levels in diabetic rodents. This remarkable cure of diabetes mellitus is mediated by astrocytes. The most prominent genes activated by FGF-1 treatment include the genes responsible for the synthesis of FABP6 and FABP7 by astrocytes.[84] These data confirm the importance of FABP7+ astrocytes for the control of blood glucose. Dysfunction of FABP7+/Gomori-positive astrocytes may contribute to the aging-related development of diabetes mellitus.

GP astrocytes are also present in the dentate gyrus of the hippocampus in both rodent and human brains.[85] The hippocampus undergoes severe degenerative changes during aging in Alzheimer's disease. The reasons for these degenerative changes are currently being hotly debated. A recent study has shown that levels of glial proteins, and NOT neuronal proteins, are most abnormal in Alzheimer's disease. The glial protein most severely affected is FABP5.[86] Another study showed that 100% of hippocampal astrocytes that contain FABP7 also contain FABP5.[87] These data suggest that FABP7+/Gomori-positive astrocytes may play a role in Alzheimer's disease. An altered glial function in this region could compromise the function of dentate gyrus neurons and also the function of axons that terminate in the dentate gyrus. Many such axons originate in the lateral entorhinal cortex, which is the first brain region to show degeneration in Alzheimer's disease. Astrocyte pathology in the hippocampus thus might make a contribution to the pathology of Alzheimer's disease.

Research

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A study performed in November 2010 and published March 2011, was done by a team of scientists from the University of Rochester and University of Colorado School of Medicine. They did an experiment to attempt to repair trauma to the Central Nervous System of an adult rat by replacing the glial cells. When the glial cells were injected into the injury of the adult rat's spinal cord, astrocytes were generated by exposing human glial precursor cells to bone morphogenetic protein (bone morphogenetic protein is important because it is considered to create tissue architecture throughout the body). So, with the bone protein and human glial cells combined, they promoted significant recovery of conscious foot placement, axonal growth, and obvious increases in neuronal survival in the spinal cord laminae. On the other hand, human glial precursor cells and astrocytes generated from these cells by being in contact with ciliary neurotrophic factors, failed to promote neuronal survival and support of axonal growth at the spot of the injury.[88]

One study done in Shanghai had two types of hippocampal neuronal cultures: In one culture, the neuron was grown from a layer of astrocytes and the other culture was not in contact with any astrocytes, but they were instead fed a glial conditioned medium (GCM), which inhibits the rapid growth of cultured astrocytes in the brains of rats in most cases. In their results they were able to see that astrocytes had a direct role in Long-term potentiation with the mixed culture (which is the culture that was grown from a layer of astrocytes) but not in GCM cultures.[89]

Studies have shown that astrocytes play an important function in the regulation of neural stem cells. Research from the Schepens Eye Research Institute at Harvard shows the human brain to abound in neural stem cells, which are kept in a dormant state by chemical signals (ephrin-A2 and ephrin-A3) from the astrocytes. The astrocytes are able to activate the stem cells to transform into working neurons by dampening the release of ephrin-A2 and ephrin-A3.[90]

In a study published in a 2011 issue of Nature Biotechnology[91] a group of researchers from the University of Wisconsin reports that it has been able to direct embryonic and induced human stem cells to become astrocytes.

A 2012 study[92] of the effects of marijuana on short-term memories found that THC activates CB1 receptors of astrocytes which cause receptors for AMPA to be removed from the membranes of associated neurons.

A 2023 study[93] showed that astrocytes also play an active role in Alzheimer's disease. More specifically, when astrocytes became reactive they unleash the pathological effects of amyloid-beta on downstream tau phosphorylation and deposition, which very likely will lead to cognitive deterioration.

Classification

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There are several different ways to classify astrocytes.

Lineage and antigenic phenotype

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These have been established by classic work by Raff et al. in early 1980s on Rat optic nerves.

  • Type 1: Antigenically Ran2+, GFAP+, FGFR3+, A2B5−, thus resembling the "type 1 astrocyte" of the postnatal day 7 rat optic nerve. These can arise from the tripotential glial restricted precursor cells (GRP), but not from the bipotential O2A/OPC (oligodendrocyte, type 2 astrocyte precursor, also called Oligodendrocyte progenitor cell) cells.
  • Type 2: Antigenically A2B5+, GFAP+, FGFR3−, Ran 2−. These cells can develop in vitro from the either tripotential GRP (probably via O2A stage) or from bipotential O2A cells (which some people{{[94]}} think may in turn have been derived from the GRP) or in vivo when these progenitor cells are transplanted into lesion sites (but probably not in normal development, at least not in the rat optic nerve). Type 2 astrocytes are the major astrocytic component in postnatal optic nerve cultures that are generated by O2A cells grown in the presence of fetal calf serum but are not thought to exist in vivo.[95]

Anatomical classification

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  • Protoplasmic: found in grey matter and have many branching processes whose end-feet envelop synapses. Some protoplasmic astrocytes are generated by multipotent subventricular zone progenitor cells.[96][97]
  • Gömöri-positive astrocytes. These are a subset of protoplasmic astrocytes that contain numerous cytoplasmic inclusions, or granules, that stain positively with Gömöri trichrome stain a chrome-alum hematoxylin stain. It is now known that these granules are formed from the remnants of degenerating mitochondria engulfed within lysosomes,[98] Some type of oxidative stress appears to be responsible for the mitochondrial damage within these specialized astrocytes. Gömöri-positive astrocytes are much more abundant within the arcuate nucleus of the hypothalamus and in the hippocampus than in other brain regions. They may have a role in regulating the response of the hypothalamus to glucose.[99][100]
  • Fibrous: found in white matter and have long thin unbranched processes whose end-feet envelop nodes of Ranvier. Some fibrous astrocytes are generated by radial glia.[101][102][103][104][105]

Transporter/receptor classification

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  • GluT type: these express glutamate transporters (EAAT1/SLC1A3 and EAAT2/SLC1A2) and respond to synaptic release of glutamate by transporter currents. The function and availability of EAAT2 is modulated by TAAR1, an intracellular receptor in human astrocytes.[106]
  • GluR type: these express glutamate receptors (mostly mGluR and AMPA type) and respond to synaptic release of glutamate by channel-mediated currents and IP3-dependent Ca2+ transients.

See also

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References

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Further reading

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Astrocyte

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Astrocytes are star-shaped glial cells that constitute a major component of the (CNS), comprising approximately 20-40% of all cells (astrocyte-to-neuron ratio ∼0.7:1 in the ) and occupying 25-50% of the 's volume. Named after their characteristic morphology by Mihaly von Lenhossek in 1895, these ectodermal-derived cells form non-overlapping domains that tile the entire CNS, providing essential structural and metabolic support to neurons while actively participating in information processing. In healthy brains, astrocytes maintain by regulating balance, , and levels, and they form tripartite synapses with pre- and postsynaptic neuronal elements, influencing and transmission. Morphologically, astrocytes exhibit diverse subtypes, including protoplasmic astrocytes in gray matter with bushy, highly branched processes that envelop synapses and vessels, and fibrous astrocytes in with elongated, less ramified extensions aligned along axonal tracts. A single protoplasmic astrocyte can contact hundreds of neuronal dendrites and up to 100,000 synapses in or over 2 million in humans, facilitated by fine perisynaptic processes (PAPs) that contain machinery and enable dynamic interactions. These cells express (GFAP) as a key cytoskeletal marker, though GFAP-negative populations highlight their heterogeneity across regions. Astrocytes are interconnected via gap junctions, allowing synchronized calcium waves and coordinated responses across networks. Functionally, astrocytes support neuronal activity through multiple mechanisms, including the uptake and recycling of neurotransmitters like glutamate via transporters such as GLT-1, which prevents excitotoxicity and shapes synaptic signaling. They store glycogen as an energy reserve, releasing lactate and other metabolites to fuel neurons during high-demand periods or hypoglycemia, thus linking neuronal metabolism to cerebral blood flow regulation. Beyond support, astrocytes exhibit gliotransmission by releasing signaling molecules like glutamate, ATP, and D-serine in response to calcium transients, modulating synaptic strength and contributing to processes such as long-term potentiation (LTP). Their processes also form endfeet that maintain the blood-brain barrier (BBB) integrity, provide neurotrophic factors, and detoxify reactive oxygen species, underscoring their role in CNS defense and repair. In addition to static functions, astrocytes display structural plasticity, with PAPs extending or retracting in response to sensory stimuli, learning, or circadian rhythms, thereby fine-tuning neural circuits and behaviors like formation. This adaptability positions astrocytes as active partners in brain dynamics, with disruptions linked to neurological disorders, though their precise contributions in pathology remain under investigation.

Structure and Morphology

General Morphology

Astrocytes are star-shaped glial cells distinguished by a central cell body, or soma, from which numerous primary processes radiate outward, creating a stellate morphology that facilitates extensive interactions within the . These processes branch into finer secondary and tertiary extensions, allowing astrocytes to form a supportive network around neurons and vasculature. The overall structure enables astrocytes to occupy non-overlapping territorial domains in the brain parenchyma, with each astrocyte typically spanning tens to hundreds of micrometers depending on species and region. Key cellular components of astrocytes include a prominent, euchromatic nucleus within the soma, indicative of high transcriptional activity, surrounded by containing mitochondria, , and other organelles essential for metabolic support. The is reinforced by intermediate filaments, notably (GFAP), which provides mechanical stability to the processes and serves as a hallmark marker for astrocyte identification. Intercellular communication occurs through gap junctions composed of proteins, such as connexin 43 (Cx43), which couple adjacent astrocytes into functional syncytia. Astrocytes exhibit specialized domain organization, with perisynaptic processes that envelop neuronal —often wrapping up to 60-90% of synaptic surfaces in certain regions—and vascular endfeet that form tight sheaths around capillaries. These endfeet cover approximately 99% of the cerebral vascular surface, integrating astrocytes into the neurovascular unit. This arrangement positions astrocytes at the interface of the tripartite , where they interact with pre- and postsynaptic elements. Historically, these cells were first described by Otto Deiters in 1865 as elements with a central nucleus and radiating fiber tracts, based on his microscopic examinations of mammalian tissue.

Protoplasmic Astrocytes

Protoplasmic astrocytes are primarily located in the gray matter of the cerebral and cerebellar cortices, where they form a key component of the neuropil. These cells exhibit a highly branched morphology characterized by numerous short, velate processes that emanate from the soma, creating a spongy, sponge-like network that tiles non-overlapping territories within the tissue. This intricate arborization allows individual protoplasmic astrocytes to occupy distinct domains, interacting with neighboring astrocytes only at their peripheral edges to ensure comprehensive coverage of the local environment. A distinguishing feature of protoplasmic astrocytes is their extensive association with synapses, with each cell capable of ensheathing up to 100,000 synaptic contacts in . These processes often form leaf-like expansions that closely appose neuronal elements, including dendritic spines and terminals, facilitating intimate structural interactions at and synapses throughout the gray matter. In contrast to fibrous astrocytes, which predominate in tracts and exhibit straighter processes aligned with myelinated fibers, protoplasmic astrocytes display lower levels of (GFAP) expression, reflecting their adapted morphology for synaptic proximity rather than axonal support.

Fibrous Astrocytes

Fibrous astrocytes are primarily located in regions of the , such as the , optic tract, and , where they align with myelinated axonal tracts. These cells exhibit an elongated morphology characterized by a central cell body from which extend fewer but longer processes compared to protoplasmic astrocytes, with reduced branching complexity suited to the linear organization of white matter. Their processes are rich in intermediate filaments, particularly (GFAP), which is highly expressed and serves as a key immunohistochemical marker for identifying these cells. The fibrous processes of these astrocytes form dense bundles that run parallel to myelinated axons, providing structural support and facilitating homeostasis along pathways. These processes often terminate at or contact nodes of Ranvier, the gaps between myelin sheaths where action potentials are generated, thereby contributing to the maintenance of axonal integrity and . In terms of , fibrous astrocytes display less territorial exclusivity than their gray matter counterparts, with processes showing considerable overlap among neighboring cells, which allows for coordinated coverage of extensive volumes. Quantitatively, individual fibrous astrocytes in human can span larger domains, with processes extending up to 100-200 μm in length and each cell reflecting their adaptation to the sparser cellular density of white matter (approximately 79 cells/mm² in the ). This extended reach enables them to interact with multiple axons over greater distances, underscoring their role in supporting the efficiency of long-range neural signaling.

Radial Glia

Radial glia represent a transient subtype of astrocytes that serve as scaffold-like cells during embryonic development, characterized by their elongated morphology and strategic positioning within the . These cells are distributed throughout the embryonic , with their somata primarily located in the ventricular zone and extending processes that span from the ventricular surface to the pial surface, thereby bridging the developing cortical layers. The defining morphology of radial glia includes long radial processes that can extend up to 1 mm or more in length, forming a palisade-like arrangement that provides structural support across the neural epithelium. These processes originate from the ovoid cell body near the ventricular zone, featuring a short apical process terminating in an endfoot at the ventricle and a longer basal process that reaches the pial surface, often branching into multiple endfeet for attachment. Radial glia express specific markers that reflect their developmental stage, such as in early phases, which transitions to (GFAP) expression as progresses. Their somata reside in the ventricular zone, and their radial processes facilitate the guidance of neuronal migration during corticogenesis. Following the completion of , many radial glia differentiate into mature astrocytes in the postnatal period, while some retain radial-like features in specific adult regions, such as Bergmann glia in the .

Classification

Lineage and Antigenic Markers

Astrocytes primarily derive from neuroepithelial progenitors located in the embryonic ventricular zone, which transition into radial cells that serve as intermediate progenitors for both neurons and . These radial cells generate the majority of cortical astrocytes through asymmetric divisions, particularly during late when they switch from producing neurons to glial cells. Additionally, a subset of astrocytes arises from progenitors in the , including bipotent precursors that can differentiate into both astrocytes and . Key antigenic markers facilitate the identification and classification of astrocytes based on their protein expression profiles. (GFAP), an protein, is a widely used marker that becomes upregulated during astrocyte maturation and is particularly prominent in reactive states. Aldehyde dehydrogenase 1 family member L1 (ALDH1L1) serves as a pan-astrocyte marker, expressed in nearly all mature astrocytes regardless of subtype or region, making it highly selective for astrocyte identification. S100B, a , is another common marker that highlights astrocyte cell bodies and is often used in conjunction with GFAP and ALDH1L1 for comprehensive labeling. Antigenic phenotypes distinguish astrocyte subtypes, with Type I astrocytes originating from and exhibiting a protoplasmic or fibrous morphology, characterized by GFAP positivity and absence of A2B5 expression. Regional variations in these phenotypes are evident, such as higher GFAP expression in astrocytes compared to gray matter protoplasmic types, reflecting adaptations to local tissue demands. Note that distinctions like A2B5 expression are more prominent in developmental or contexts, while classifications increasingly rely on transcriptomic profiles. The use of GFAP as an astrocyte marker originated in the 1970s, when it was isolated from plaques and recognized as a specific indicator of astroglial cells, revolutionizing neuropathological diagnostics. Advances in single-cell sequencing during the 2020s have further illuminated astrocyte heterogeneity, revealing diverse transcriptional states and subtypes beyond traditional markers, including region-specific clusters with varying progenitor origins and functional specializations such as disease-associated reactive states.

Anatomical Features

Astrocytes are classified anatomically based on their location within the brain's gray and . Protoplasmic astrocytes, characterized by their bushy processes, predominate in gray matter regions, where they form intimate associations with synaptic domains. In contrast, fibrous astrocytes, with their elongated, less branched processes, are primarily located in , aligning closely with bundles of myelinated axons. This positional distinction reflects adaptations to the distinct structural demands of neuronal elements in these compartments. A key anatomical feature of astrocytes is their territorial organization, in which individual cells establish non-overlapping domains that tile the parenchyma. These domains allow each astrocyte to cover a , with processes from neighboring cells rarely overlapping, ensuring efficient partitioning of neural space. For example, in cortical regions, a single astrocyte's territory typically encompasses thousands to hundreds of thousands of synapses belonging to hundreds (e.g., 300-600) of neuronal processes. Collectively, the processes of astrocytes occupy approximately 20-40% of the brain's volume, contributing substantially to the neuropil's architecture. Regional variations in astrocyte anatomy further highlight their positional diversity. In the , Bergmann glia represent a specialized radial subtype, extending pial-directed processes that provide structural support to Purkinje cells and guide migration. Similarly, in the , Müller glia function as elongated radial astrocytes that span all retinal layers, from the inner limiting membrane to the outer limiting membrane, maintaining retinal lamination and . Quantitative assessments of astrocyte distribution reveal species-specific differences in density and ratios. In the , the astrocyte-to-neuron ratio is approximately 1:1, though this varies by region and species. In humans, this ratio is approximately 1:1.4, higher than the roughly 1:3 ratio observed in brains, reflecting an evolutionary expansion of astrocyte populations documented in studies from the . This increase underscores the scaling of glial support with neuronal complexity in larger brains.

Molecular Transporters and Receptors

Astrocytes express a diverse array of molecular transporters and receptors that underpin their involvement in neuronal signaling and brain homeostasis. Key transporters include the excitatory transporters EAAT1 (also known as GLAST) and EAAT2 (GLT-1), which are predominantly localized to astrocytic membranes surrounding synapses and mediate the rapid uptake of glutamate to regulate extracellular levels. Inwardly rectifying (Kir) channels, particularly the Kir4.1 subtype, are enriched in astrocyte processes and perisynaptic regions, facilitating the spatial buffering of ions to maintain extracellular balance during synaptic activity. Neurotransmitter receptors on astrocytes enable detection of synaptic signals and reciprocal communication. Metabotropic glutamate receptors (mGluRs), such as group I subtypes (mGluR1 and mGluR5), are expressed in astrocytic membranes and respond to glutamate to mobilize intracellular calcium, supporting astrocyte-neuron interactions. GABA receptors, including GABA_B subtypes, allow astrocytes to sense inhibitory neurotransmission and modulate their own excitability. Purinergic receptors, notably P2Y1, detect extracellular ATP and trigger calcium-dependent responses that contribute to gliotransmission. Transcriptomic analyses in the 2020s have highlighted astrocyte heterogeneity through differential expression of these molecules, enabling classification into subtypes with varying functional specializations; for example, some populations show high EAAT expression suited for synaptic glutamate clearance, while others exhibit lower levels potentially emphasizing metabolic roles. This molecular diversity is further exemplified by aquaporin-4 (AQP4), a channel protein concentrated in perivascular astrocyte endfeet to regulate water flux at the blood-brain interface. Connexin 43 (Cx43), the dominant connexin isoform in astrocytes, forms gap junctions that couple cells into syncytia, permitting the passage of ions and metabolites for coordinated network responses.

Development

Embryonic Origin

Astrocytes originate from neuroepithelial cells lining the during early embryogenesis. In mice, these progenitors emerge around embryonic day 8 (E8) to E10, initially undergoing symmetric divisions to expand the progenitor pool before transitioning to asymmetric divisions that generate neurons first and later. This process is conserved across mammals, with equivalents occurring during the first trimester, when the closes and differentiates into the . The switch from to gliogenesis is facilitated by the activation of Notch signaling, which inhibits neuronal differentiation and promotes glial fate commitment in these progenitors through the release of the Notch intracellular domain (NICD) and subsequent via RBPJ. The onset of gliogenesis is tightly regulated by key transcription factors, including and nuclear factor I-A/B (NFIA/B), which coordinate a regulatory cascade in models. is induced early, around E9.5–E11.5 in mice, where it directly activates NFIA expression via enhancer elements, marking the initiation of astrocyte precursor formation around E11.5–E12.5 in the and extending to E12–E14 in the cortex. NFIA, acting downstream and in complex with , drives the expression of glial-specific genes such as Gfap and cooperates to establish astroglial identity, ensuring the proper timing of this fate switch. These factors are essential for transforming neuroepithelial-derived progenitors into committed glial cells. Astrocyte progenitors in the ventricular zone of the undergo regional specification influenced by morphogen gradients, such as Sonic hedgehog (Shh) and bone morphogenetic proteins (BMPs), which pattern distinct domains and direct subtype diversity. In the cortex, these progenitors give rise to parenchymal astrocytes, with gliogenesis initiating around E11.5 and continuing into later embryonic stages, while astrocytes emerge earlier, patterned into ventral subtypes (e.g., VA1–VA3) by combinatorial transcription factors like and Nkx6.1. This spatiotemporal variation ensures region-specific astrocyte populations aligned with local neuronal circuits. In humans, gliogenesis extends significantly into the postnatal period compared to , with substantial astrocyte generation occurring after birth through local proliferation of differentiated precursors, contributing to the expanded glial-to-neuronal ratio and larger observed in the . This prolonged timeline, supported by studies from 2012 onward, allows for greater experience-dependent refinement of astrocytic networks.

Differentiation and Maturation

Astrocyte precursors, primarily derived from radial glia through asymmetric division, undergo gliogenesis predominantly in the postnatal period. In rodents, this process peaks between postnatal day 0 (P0) and P10, with radial glia in the ventricular zone generating glioblasts that migrate and differentiate into astrocytes, contributing to the majority of the astrocyte population by P28. In humans, astrocyte generation largely completes by gestational week 30–40, but maturation extends into the first two years postnatal, aligning with ongoing and circuit refinement. Key regulatory signals drive the expression of maturation markers such as (GFAP). (BMP) signaling, via the Smad1/5/8 pathway, promotes morphological maturation and upregulates GFAP in immature astrocytes during early postnatal stages (P0–P7), while also limiting proliferation to favor differentiation. Similarly, transforming growth factor-β (TGF-β) activates the GFAP promoter, enhancing its expression and supporting astrocyte reactivity and maturity. Thyroid (T3) influences maturation timing by facilitating the transition from fetal to adult astrocyte phenotypes, regulating , , and functional specialization in postnatal development. Postnatal differentiation reveals emerging heterogeneity, with regional variations in maturation dynamics; for instance, cortical astrocytes proliferate and mature earlier than subcortical counterparts like those in the , where proliferation peaks later (P15–P30) and domain sizes remain smaller. Hippocampal astrocytes exhibit delayed maturation compared to cortical ones, contributing to region-specific functional profiles. Quantitatively, astrocyte numbers in the cortex increase six- to eight-fold during the first three postnatal weeks, reflecting robust gliogenesis. Recent studies highlight sex-specific differences, with showing accelerated maturation peaking at P7 and P14 due to perinatal testosterone effects on , while females display enhanced responsiveness influencing proliferation and . Injury-induced reactive changes can accelerate this differentiation, promoting faster GFAP expression and extension in precursors.

Functions

Structural and Synaptic Support

Astrocytes provide essential structural support to the by forming a scaffold that stabilizes neuronal elements, particularly at synapses. Their fine processes, known as perisynaptic astrocytic processes, ensheath synaptic structures, enveloping both pre- and postsynaptic components to maintain architectural integrity. This ensheathment helps stabilize dendritic spines, the postsynaptic sites of excitatory synapses, by promoting their maturation and preventing excessive motility during . Additionally, astrocytes contribute to the maintenance of the (ECM) surrounding synapses through the secretion of proteoglycans, such as proteoglycans, which provide structural rigidity and modulate neuronal adhesion. A key aspect of this structural role is the integration of astrocytes into the tripartite synapse, a functional unit comprising presynaptic terminals, postsynaptic densities, and astrocytic processes. This concept, formalized by Araque et al. in 1999, highlights how astrocytes actively participate in synaptic by detecting neuronal activity through in their processes. Each astrocyte can contact up to 100,000 synapses in and over 2 million in humans, allowing a single cell to influence vast networks of synaptic interactions. Astrocytic processes respond to synaptic activation by propagating calcium waves, which enable the cell to sense and modulate synaptic strength without directly altering neuronal firing. Astrocytes further support synaptic function through specific mechanisms that regulate the synaptic microenvironment. They facilitate perisynaptic uptake and trapping of neurotransmitters, such as glutamate, via transporters like EAAT1 and EAAT2 located on their processes, thereby preventing spillover and maintaining precise signaling. Moreover, astrocytes contribute to extracellular volume regulation by buffering ions and osmolytes, which helps prevent synaptic and preserves the narrow extracellular spaces essential for efficient around synapses. This volume control is mediated by channels like aquaporin-4 and channels, ensuring during periods of heightened activity.

Gliotransmission

Astrocytes engage in gliotransmission by releasing signaling molecules that actively modulate neuronal excitability and synaptic function within the tripartite synapse framework. This process involves the calcium-dependent of gliotransmitters such as glutamate, ATP, and D-serine from vesicular compartments, enabling astrocytes to influence neuronal networks independently of direct synaptic input. The primary mechanism of gliotransmitter release in astrocytes is calcium-dependent vesicular , mediated by SNARE proteins that facilitate vesicle fusion with the plasma membrane. Seminal studies demonstrated that elevations in intracellular calcium trigger the release of glutamate from astrocytes, requiring SNARE complex formation involving proteins like VAMP2 and syntaxin-4. Similar vesicular mechanisms apply to ATP and D-serine, where calcium influx promotes the docking and fusion of secretory vesicles containing these molecules. While early evidence supported this exocytotic pathway, the 2010s literature debated the predominance of vesicular versus non-vesicular release routes, such as transporter reversal or channel-mediated efflux; however, high-resolution imaging and genetic studies have since affirmed calcium-triggered vesicular as a key regulated process in intact brain tissue. Glutamatergic gliotransmission exemplifies this process, as astrocytes release glutamate to activate neuronal NMDA receptors, thereby enhancing and . This release occurs focally near synapses, allowing precise modulation of neuronal calcium influx and trafficking without spillover artifacts. For D-serine, astrocytes serve as a primary source, co-agonizing NMDA receptors to gate synaptic NMDA currents and support memory-related plasticity. ATP release from astrocytes, often via pannexin-1 hemichannels or vesicles, undergoes ecto-enzymatic to , which binds A1 receptors on neurons to dampen excitability and provide during prolonged activity. Gliotransmission is tightly regulated by synaptic activity, particularly through metabotropic glutamate receptors (mGluRs) on astrocytes that detect glutamate spillover and initiate intracellular calcium waves. Activation of group I mGluRs, such as mGluR5, couples to , generating IP3 to release calcium from stores and trigger . This feedback loop ensures gliotransmitter release scales with neuronal firing rates, maintaining synaptic .

Metabolic and Energy Support

Astrocytes play a pivotal role in energy by serving as the primary site for and processing, which supports neuronal energy demands through the astrocyte-neuron lactate shuttle (ANLS). In this mechanism, glutamate released from active neurons is taken up by astrocytes via excitatory amino acid transporters, stimulating aerobic glycolysis within astrocytes despite sufficient oxygen availability. This process leads to the production of lactate from glucose, which is then exported to neurons for oxidation in mitochondria to generate ATP, coupling neuronal activity directly to energy substrate provision. The ANLS was first proposed by Pellerin and Magistretti in 1994 based on evidence showing that glutamate uptake increases glycolytic flux in astrocytes, with lactate serving as the preferred energy substrate for neurons under high activity conditions. Key to the ANLS is the compartmentalization of metabolic enzymes and transporters: astrocytes express high levels of lactate dehydrogenase isoform LDHA, favoring lactate production, and monocarboxylate transporters MCT1 and MCT4 for lactate export, while neurons express LDHB and MCT2 for efficient uptake and utilization. During periods of increased neural activity, this shuttle ensures rapid energy supply, as lactate can be oxidized more quickly than glucose in neurons. Astrocytes access glucose primarily through glucose transporter 1 (GLUT1) at the blood-brain barrier interface, facilitating the initial uptake step in this metabolic pathway. Astrocytes also maintain brain energy reserves by storing the majority of cerebral , primarily in their processes. in astrocytes acts as a dynamic buffer, mobilized during synaptic activity or energy deficits to replenish lactate via anaerobic glycolysis. The core reaction involves the breakdown of to glucose-1-phosphate, followed by yielding lactate and net ATP production, as represented by the simplified equation for anaerobic glycolysis: Glucose+2ADP+2Pi+2NAD+→2Lactate+2ATP+2NADH+2H+\text{Glucose} + 2 \text{ADP} + 2 \text{P}_i + 2 \text{NAD}^+ \rightarrow 2 \text{Lactate} + 2 \text{ATP} + 2 \text{NADH} + 2 \text{H}^+ This process generates 2 ATP per glucose molecule under anaerobic conditions, supporting short-term energy needs when oxidative is limited. Astrocytic is regulated by adrenergic and signaling, ensuring timely release of lactate to sustain neuronal function during or ischemia. Beyond carbohydrates, astrocytes contribute to by synthesizing and phospholipids essential for neuronal membrane maintenance and formation. Astrocytes are the primary source of in the , exporting it via apolipoprotein E (apoE)-containing lipoproteins to and neurons, which lack the capacity for de novo synthesis. This supports sheath production, where phospholipids like are also provided by astrocytes to during myelination. In states of , astrocytes metabolize derived from peripheral , converting them into energy substrates or further processing them for neuronal use, thereby adapting to glucose scarcity. Recent studies highlight astrocytes' ability to produce locally from fatty acids, fueling neurons and maintaining during prolonged . Emerging research from 2022 to 2025 emphasizes the role of astrocyte mitochondrial dynamics in managing (ROS) during energy crises, such as or ischemia. Mitochondrial fission and fusion, mediated by proteins like Drp1 and OPA1, allow astrocytes to adapt by segregating damaged mitochondria for mitophagy, thereby mitigating ROS-induced that could impair lactate production. This dynamic regulation preserves astrocyte metabolic support to neurons, with disruptions linked to impaired energy provisioning in metabolic stress. For instance, enhanced fission promotes ROS clearance, enabling sustained and mobilization under low-energy conditions.

Blood-Brain Barrier Maintenance

Astrocytes play a crucial role in the formation and maintenance of the blood-brain barrier (BBB) through their perivascular endfeet, which extensively cover the abluminal surface of brain capillaries and form the , providing and regulating endothelial permeability. These endfeet processes ensheath over 99% of the vascular surface in mature brains, facilitating direct communication with endothelial cells to induce and sustain barrier properties. Astrocytes secrete signaling molecules such as and sonic hedgehog (SHH), which promote the assembly of tight junctions in endothelial cells by upregulating proteins like claudin-5 and . For instance, SHH signaling from astrocytes activates the and receptors on endothelial cells, enhancing barrier integrity independently of . VEGF, while potentially increasing permeability at high levels, works in concert with angiopoietin-1 to stabilize junctions when secreted by astrocytes. In addition to structural support, astrocytes maintain and homeostasis at the BBB through polarized expression of aquaporin-4 (AQP4) channels in their endfeet, which facilitate water movement and prevent formation. AQP4 is anchored to the perivascular via interactions with laminins and dystrophin-associated proteins, ensuring its localization for efficient . Coupled with inward-rectifying channels (Kir4.1), AQP4 enables potassium siphoning, where excess K⁺ from synaptic activity is taken up by astrocytic processes and redistributed to perivascular spaces, thereby stabilizing extracellular ionic balance and protecting the BBB from osmotic stress. This mechanism is essential for controlling and maintaining the electrochemical environment necessary for neuronal function. Astrocytes also regulate nutrient transport across the BBB by inducing the expression of key transporters in endothelial cells, ensuring selective passage of essential molecules while excluding toxins. They promote the upregulation of on the endothelial luminal membrane via secreted factors like transforming growth factor-β (TGF-β), facilitating glucose influx to meet cerebral energy demands. Similarly, astrocytes drive the expression of ATP-binding cassette (ABC) transporters, such as (P-gp/ABCB1), through signaling pathways involving (LIF), enabling active efflux of waste products and xenobiotics to maintain brain . The developmental maturation of the BBB coincides with the extension and coverage of astrocytic endfeet on vessels, a process that begins in late embryonic stages in , with significant coverage achieved by embryonic day 18 (E18), leading to enhanced formation and transporter expression. In humans, this process extends into the postnatal period, with full endfeet ensheathment occurring over months to years, reflecting the more protracted neurovascular development. Recent human (iPSC) models have revealed delays in astrocyte endfeet formation and BBB maturation in neurodevelopmental disorders, such as , where impaired WNT signaling disrupts barrier induction.

Immune and Inflammatory Roles

Astrocytes contribute to immune surveillance in the (CNS) by acting as antigen-presenting cells during inflammatory conditions. Under stimulation by interferon-gamma (IFNγ) from T helper 1 (Th1) cells, astrocytes upregulate (MHC) class I and II molecules, enabling them to present antigens to CD8+ and CD4+ T cells, respectively. This process facilitates direct interactions between astrocytes and T cells, which can amplify or modulate immune responses depending on the context. Additionally, activated astrocytes release pro-inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), often triggered by T cell-derived (GM-CSF), thereby promoting and potentially exacerbating CNS pathology. In response to CNS injury or infection, astrocytes undergo reactive astrogliosis, a dynamic process characterized by cellular and upregulation of (GFAP). This transformation involves morphological changes, including thickened processes and increased cell body size, mediated by signaling pathways such as signal transducer and activator of transcription 3 () and triggers like IL-6. Reactive astrocytes proliferate and migrate to form glial scars that physically isolate damaged tissue, limiting the spread of inflammatory mediators and immune cells while preserving surrounding healthy areas. Although beneficial in the acute phase for containing , prolonged glial scarring can impede axonal regeneration and neural repair. Astrocytes also participate in the complement system, primarily by synthesizing (C3), which plays a key role in and immune modulation. C3 deposited on synapses tags them for elimination by via complement receptor 3 (CR3), a process essential for refining neural circuits during development and . Furthermore, astrocyte-derived C3 and its activation products, such as C3a, enhance microglial and activation, thereby coordinating glial responses to maintain CNS immune balance or amplify as needed. Recent studies have highlighted astrocyte heterogeneity in neuroinflammatory contexts, particularly in severe acute respiratory syndrome coronavirus 2 () infection. In a 2025 of patients, infection of human induced pluripotent stem cell-derived astrocytes induced heterogeneous pro-inflammatory responses, including elevated IL-6 and IL-15 expression alongside increased , contributing to neurological symptoms like brain fog and headaches without requiring viral replication. Sex differences further influence astrocyte-mediated immune responses, with males often displaying heightened inflammatory profiles. For instance, male astrocytes exhibit stronger production (e.g., higher IL-6, TNF-α, and IL-1β) following (LPS) exposure compared to females, while in females attenuates TNF-α and IL-18 expression during . In injury models like , female astrocytes show more frequent events, and aged females display elevated levels, underscoring sex-specific vulnerabilities in astrocyte reactivity.

Role in Disease

Astrocytomas

Astrocytomas are a diverse group of primary tumors that arise from astrocytes or their precursor cells, representing the most common type of . These tumors span a spectrum from low-grade forms, such as pilocytic astrocytoma classified as WHO CNS grade 1, to high-grade malignancies like (GBM), designated as WHO CNS grade 4. Low-grade astrocytomas, including pilocytic variants, typically exhibit circumscribed growth and are more prevalent in children, while high-grade forms such as GBM demonstrate aggressive, infiltrative behavior predominantly in adults. The origin of astrocytomas is linked to genetic alterations in astrocyte precursors, with mutations in the IDH1 gene serving as an early driver event in the development of most low- and intermediate-grade tumors. IDH1 mutations, particularly the R132H variant, occur in over 70% of grade 2 and 3 astrocytomas, promoting metabolic reprogramming that facilitates neoplastic transformation from glial progenitors. In contrast, IDH-wildtype astrocytomas, including the majority of GBMs, arise de novo without these mutations and are associated with rapid progression. Astrocytomas account for approximately 30% of all gliomas, with GBM comprising the largest subset among malignant cases. Pathophysiologically, astrocytomas are characterized by uncontrolled cellular proliferation due to dysregulated signaling pathways, such as those involving EGFR and PTEN, leading to hyperactivation of PI3K/AKT and MAPK cascades. Tumor cells extend invasive processes along tracts and the brain's perivascular spaces, evading immune surveillance and contributing to recurrence. Additionally, tumor-associated astrocytes and glioma cells secrete vascular endothelial growth factor (VEGF), which drives pathological by stimulating endothelial cell proliferation and new vessel formation, thereby supporting the tumor's hypoxic microenvironment and metastatic potential. This angiogenic switch is particularly pronounced in high-grade astrocytomas, where VEGF expression correlates with increased and . The (WHO) 2021 classification integrates histopathological features with s for precise grading of s, emphasizing IDH mutation status, 1p/19q codeletion, and variants to distinguish astrocytoma subtypes from oligodendrogliomas. For instance, IDH-mutant astrocytomas are graded from 2 to 4 based on features like mitotic activity and microvascular proliferation, while IDH-wildtype diffuse astrocytic tumors with specific alterations (e.g., EGFR amplification) are directly classified as GBM, grade 4. promoter methylation, though not definitional for grading, serves as a key predicting response to alkylating agents like , with methylated status associated with improved outcomes in GBM patients. Epidemiologically, astrocytomas predominantly affect adults, with peak incidence in the 45-65 age group for high-grade forms, and they constitute a significant burden due to limited therapeutic . For GBM, the median survival remains approximately 15 months even with standard treatment involving , radiotherapy, and , highlighting the tumor's resistance and infiltrative nature. In some contexts, the expression and hypertrophic morphology in astrocytomas mimic reactive , underscoring shared molecular pathways in astrocyte responses to .

Neurodevelopmental Disorders

Astrocytes play a critical role in brain development, and their dysfunction contributes to various neurodevelopmental disorders, including autism spectrum disorder (ASD) and . Postmortem examinations of individuals with ASD have revealed reduced astrocyte density in the , alongside signs of increased astrocyte activation, potentially disrupting synaptic connectivity and neuronal communication. In , mutations in the MECP2 gene lead to astrocyte abnormalities, including altered expression of , a key marker of astrocyte structure and function; MeCP2 deficiency in astrocytes impairs their support for neuronal health and exacerbates disease progression. These findings highlight how early disruptions in astrocyte maturation and density during development can precipitate long-term neurodevelopmental impairments. Mechanistically, astrocyte abnormalities in these disorders often involve deficits in gliotransmission, which hinder critical processes such as neuronal migration and . For instance, impaired release of gliotransmitters like ATP from astrocytes disrupts signaling in the , contributing to social interaction deficits observed in ASD models. Within the tripartite synapse model—where astrocytes form a functional unit with pre- and postsynaptic —dysfunctional astrocytes alter formation by failing to properly regulate excitatory/inhibitory balance, leading to excessive or immature synaptic connections that underlie behavioral phenotypes in neurodevelopmental disorders. Evidence from animal models supports these associations; for example, astrocyte-specific conditional of the IP3R2 , which impairs essential for gliotransmission, results in mice exhibiting ASD-like behaviors such as reduced social interaction and increased repetitive actions. Similarly, MeCP2-deficient astrocytes in models demonstrate reduced support for due to aberrant secretion of factors like interleukin-6, mimicking core symptoms of the disorder. Recent genetic studies from 2023 to 2025 have further linked variants in the NR2F1 , which regulates astrocyte development through transcription factors influencing cell-intrinsic pathways, to neurodevelopmental disorders with precursors, including and psychosis-like features in Bosch-Boonstra-Schaaf optic atrophy syndrome.

Chronic Pain

Astrocytes play a pivotal role in the development and maintenance of chronic pain through reactive gliosis, particularly in the spinal cord dorsal horn, where they upregulate glial fibrillary acidic protein (GFAP) and release pro-inflammatory chemokines such as tumor necrosis factor-alpha (TNF-α). This upregulation amplifies nociceptive signaling by enhancing neuronal excitability and synaptic transmission, contributing to pain hypersensitivity. In spinal astrocytes, GFAP expression increases following peripheral nerve injury or inflammation, leading to morphological changes like hypertrophy and process retraction, which facilitate the release of these chemokines to neighboring neurons and microglia. TNF-α, in particular, sensitizes pain pathways by binding to receptors on dorsal horn neurons, promoting long-term potentiation and central pain amplification. Chronic pain involves distinct astrocyte-mediated states depending on the etiology: inflammatory pain features rapid gliosis with acute cytokine release, while neuropathic pain exhibits persistent astrocyte hyperactivity driven by ATP signaling. In inflammatory models, such as those induced by carrageenan, astrocytes undergo swift activation, releasing TNF-α and interleukin-1β within hours to days, exacerbating peripheral and central sensitization. Conversely, in neuropathic conditions like spinal nerve ligation, astrocytes maintain elevated ATP release via channels like pannexin-1, sustaining gliotransmitter spillover and neuronal hyperexcitability over weeks, which prolongs pain states. This ATP-dependent hyperactivity distinguishes neuropathic pain by fostering a feed-forward loop of astrocyte-neuron communication, independent of the initial injury. Key pathways involve astrocyte gliotransmission that enhances activity in the dorsal horn, culminating in central sensitization. Activated astrocytes release glutamate and D-serine, which bind to on postsynaptic neurons, lowering the threshold for synaptic and amplifying nociceptive inputs. A core model posits that peripheral stimuli trigger astrocyte , prompting release from primary afferents; this further stimulates astrocytes via neurokinin-1 receptors, leading to enhanced gliotransmitter output and persistent synaptic strengthening. This cycle underlies central sensitization, where normal touch evokes pain (), as astrocytes bridge peripheral signals to prolonged neuronal changes. Evidence from preclinical studies in the 2000s demonstrated that inhibiting astrocyte reduces behaviors, as seen with , a that suppresses microglial and astrocytic activation. For instance, intrathecal administration in rat models of attenuated mechanical by blocking GFAP upregulation and release in spinal astrocytes. In human studies, (fMRI) reveals correlates of astrocyte involvement in , a chronic widespread pain disorder, through altered blood-oxygen-level-dependent (BOLD) signals linked to glial calcium waves and in pain-processing regions like the insula and . These findings underscore astrocytes' therapeutic potential in modulating persistence.

Neurodegenerative Diseases

Astrocytes play a pivotal role in the pathogenesis of neurodegenerative diseases through dysregulated reactivity and impaired supportive functions, contributing to neuronal damage and disease progression. In conditions such as (AD), (ALS), and (PD), astrocyte dysfunction exacerbates , disrupts clearance mechanisms, and promotes , highlighting their transition from neuroprotective to neurotoxic states. Recent human (iPSC)-derived models have revealed sex-biased astrocyte reactivity, with female-derived astrocytes exhibiting heightened inflammatory responses and mitochondrial alterations in AD and ALS contexts, underscoring the influence of biological sex on glial contributions to neurodegeneration. In Alzheimer's disease, reactive astrocytes adopt a pro-inflammatory A1 phenotype that promotes by secreting cytokines such as IL-1β and TNF-α, which correlate with cognitive decline and plaque-associated neuronal loss. This A1 subtype is induced by microglial signals including C1q, TNF, and IL-1α, leading to the upregulation of neurotoxic factors that amplify synaptic dysfunction and pathology. Additionally, astrocyte-mediated clearance of amyloid-β (Aβ) fails due to reduced , as Aβ oligomers impair the uptake and degradation of dystrophic synapses by astrocytes, resulting in extracellular Aβ accumulation and plaque formation. Depletion of receptor-related protein 4 (LRP4) in astrocytes further disrupts Aβ , exacerbating the imbalance between production and clearance. In , astrocytes expressing mutant 1 (), such as the G85R variant, release toxic factors that induce death via glutamate-mediated . These mutant astrocytes exhibit gain-of-function , including elevated D-serine levels that co-activate NMDA receptors, and fail to buffer extracellular glutamate effectively. A key mechanism involves the loss of the excitatory transporter 2 (EAAT2), observed in 60-70% of sporadic cases, where post-transcriptional defects reduce glutamate uptake by up to 95% in affected regions, heightening vulnerability to excitotoxic damage. Emerging research highlights aquaporin-4 (AQP4) in astrocytes as a therapeutic target, with mislocalization impairing glymphatic clearance of toxic proteins; preclinical models suggest modulating AQP4 polarization could mitigate progression, though clinical translation remains in early stages as of 2024. In , astrocytes facilitate the propagation of aggregates, taking up and releasing pathological oligomers that seed further misfolding in neurons, thereby accelerating formation and spread. This intercellular transmission is mediated by vesicular release from reactive astrocytes, which also show impaired uptake of compared to healthy states. Furthermore, astrocyte dysfunction disrupts metabolism support, with PD patient-derived astrocytes displaying elevated expression and altered mitochondrial bioenergetics that reduce supply and antioxidant defense to neurons, promoting and degeneration. Loss of ATP13A2 in astrocytes compromises lysosomal degradation of , further impairing clearance and exacerbating .

Other Pathologies

In , a condition arising from liver dysfunction, astrocytes undergo characteristic morphological changes, manifesting as hypertrophied, inclusion-laden cells known historically as Gomori-positive astrocytes, which indicate metabolic stress and were first described in the using hematoxylin staining techniques. These cells, often referred to as Alzheimer type II astrocytes, feature enlarged nuclei with prominent nucleoli and cytoplasmic inclusions, reflecting impaired metabolism and osmotic dysregulation. Ammonia accumulation in induces astrocyte swelling through excessive synthesis via , leading to osmotic imbalance and cytotoxic brain . This swelling compromises astrocyte functions, including glutamate uptake and , exacerbating neuropsychiatric symptoms and potentially progressing to . Cytokines further potentiate this ammonia-induced swelling, amplifying inflammatory responses and contributing to low-grade even in chronic cases. Following or , astrocytes enter a state of reactive , forming glial scars that initially contain damage but ultimately inhibit axonal regeneration by creating physical and molecular barriers. These scars, composed of upregulated proteins like proteoglycans, impede neurite outgrowth and synaptic remodeling in the peri-injury zone. In addition, reactive astrocytes may promote post-traumatic through mechanisms involving neuronal hypersynchronization, where dysregulated gliotransmission and potassium buffering facilitate aberrant network activity. Recent 2025 research highlights astrocytes' involvement in long COVID-associated brain fog, where persistent triggers astrocyte activation, leading to dysregulation and . This chronic astrocytic response, characterized by elevated signaling and blood-brain barrier permeability, sustains microglial activation and synaptic dysfunction months post-infection.

Research Directions

Current Studies

Recent advances in astrocyte research have leveraged single-cell sequencing to uncover significant heterogeneity among astrocyte populations, revealing distinct subtypes based on transcriptional profiles across regions. For instance, the Zeisel et al. atlas from 2018 identified four broad astrocyte types across the mouse , with subsequent analyses like Batiuk et al. (2020) identifying five region-specific subtypes in the cortex and hippocampus. Additionally, 2022 interference screens in iPSC-derived astrocytes have pinpointed genetic regulators of reactive state transitions, such as those involving pathways, enabling targeted manipulation of astrocyte responses to inflammatory cues. Imaging techniques have advanced the study of astrocyte dynamics in vivo, with two-photon microscopy enabling real-time visualization of in intact brain tissue. This approach has revealed spatially restricted calcium waves in cortical astrocytes during , correlating with neuronal activity patterns. Complementing this, has been employed to selectively activate or inhibit astrocyte calcium channels, demonstrating their role in modulating gliotransmission—such as ATP release that influences —without confounding neuronal effects. Model systems have expanded to include human (iPSC)-derived astrocytes, which recapitulate patient-specific dysfunctions in neurodegenerative models like , showing altered inflammatory profiles. In parallel, models have provided insights into astrocyte development and their interactions with vascular networks. Key findings from post-2020 studies emphasize astrocytes as central hubs in brain network oscillations, with 2023 (EEG) correlations linking astrocytic calcium rhythms to periodicity in . Furthermore, research has highlighted enhanced astrocyte-neuron metabolic coupling, where astrocytes supply lactate via the astrocyte-neuron lactate shuttle to support high-energy demands during synaptic activity and plasticity.

Therapeutic Potential

Astrocytes represent a compelling target for therapeutic interventions in neurological disorders, leveraging their roles in maintaining synaptic , regulating , and supporting neuronal survival. Strategies focusing on astrocytes aim to mitigate pathological processes such as , , and , with several approaches advancing from preclinical models to clinical evaluation. Enhancing astrocyte-mediated glutamate uptake via excitatory transporter 2 (EAAT2) has been explored as a treatment for (ALS), where reduced EAAT2 expression contributes to degeneration. , a beta-lactam , upregulates EAAT2 levels in astrocytes, thereby increasing glutamate clearance. In a multi-phase conducted from 2009 to 2013 involving 458 ALS patients, intravenous ceftriaxone at 2 g twice daily was well-tolerated over 96 weeks but failed to significantly prolong survival or slow functional decline compared to , highlighting challenges in translating preclinical benefits to human outcomes. Modulation of aquaporin-4 (AQP4), the primary water channel in astrocytic endfeet, offers potential for managing brain following ischemic stroke. AQP4 facilitates water movement across the blood-brain barrier, exacerbating cytotoxic in the acute phase while aiding resolution in vasogenic later. Preclinical models demonstrate that selective AQP4 inhibitors, such as TGN-020, administered within 1 hour of stroke onset, significantly reduce and infarct size (e.g., by 25-35%) by blocking water influx into astrocytes. Similarly, trifluoperazine inhibits AQP4 polarization to perivascular membranes, decreasing swelling in early injury models without impairing long-term fluid clearance. These findings underscore the need for time-sensitive, phase-specific modulation, though no AQP4-targeted therapies have yet reached human trials. Gene therapy targeting astrocytes holds promise for neurodevelopmental disorders like , where mutations in the MECP2 gene impair astrocyte function, leading to synaptic dysfunction and seizures. (AAV) vectors driven by astrocyte-specific (GFAP) promoters enable selective MECP2 delivery to restore in . Preclinical studies in models show that astrocyte-restricted MECP2 re-expression via GFAP-Cre systems ameliorates motor deficits and significantly extends lifespan (e.g., from ~3 to 7.5 months). Building on this, phase I/II clinical trials initiated in 2023, such as Neurogene's NGN-401 (an AAV9-MECP2 vector with self-regulating EXACT technology), evaluate and tolerability in pediatric Rett patients to minimize . In 2025, interim data showed improved symptoms in low-dose cohorts but safety concerns in high-dose groups (as of November 2025). Stem cell-based therapies involving (iPSC)-derived astrocytes aim to replace dysfunctional and promote repair in traumatic and oncological conditions. In models, transplantation of human iPSC-derived astrocytes into the contused cervical region of rodents results in high graft survival, maturation into GFAP-positive cells, and preservation of phrenic innervation, leading to improved diaphragm amplitudes and respiratory function. For glioblastoma multiforme (GBM), iPSC-derived astrocytes are being investigated for their potential to modulate the , though clinical translation remains limited due to challenges like immune rejection and tumorigenicity. Emerging nanoparticle-based delivery systems enable selective modulation of astrocytes in chronic pain states, where astrocytic activation amplifies central sensitization. In 2025 preclinical studies, nanozymes—nanomaterials mimicking antioxidant enzymes—target oxidative stress in spinal astrocytes, scavenging reactive oxygen species to suppress neuroinflammation and reduce mechanical hypersensitivity in neuropathic pain models. These carriers, often lipid or polymeric nanoparticles conjugated with astrocyte-specific ligands like GFAP antibodies, improve drug bioavailability across the blood-brain barrier while minimizing off-target effects. Human trials raise ethical concerns, including equitable access, long-term genomic integration risks, and informed consent for vulnerable populations with chronic conditions, necessitating robust oversight frameworks.

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