Astrocytes (from

Ancient Greek Ancient Greek (, ; ) includes the forms of the Greek language used in ancient Greece and the classical antiquity, ancient world from around 1500 BC to 300 BC. It is often roughly divided into the following periods: Mycenaean Greek (), Greek ...

, , "star" and , , "cavity", "cell"), also known collectively as astroglia, are characteristic star-shaped glial cells in the

brain The brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head (cephalization), usually near organs for ...

and

spinal cord The spinal cord is a long, thin, tubular structure made up of nervous tissue that extends from the medulla oblongata in the lower brainstem to the lumbar region of the vertebral column (backbone) of vertebrate animals. The center of the spinal c ...

. They perform many functions, including biochemical control of

endothelial cell The endothelium (: endothelia) is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and th ...

s that form the

blood–brain barrier The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that regulates the transfer of solutes and chemicals between the circulatory system and the central nervous system ...

, 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 A scar (or scar tissue) is an area of fibrous tissue that replaces normal skin after an injury. Scars result from the biological process of wound repair in the skin, as well as in other organs, and tissues of the body. Thus, scarring is a nat ...

process of the brain and spinal cord following infection and traumatic injuries. 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. Another study reports that astrocytes are the most numerous cell type in the brain. Astrocytes are the major source of cholesterol in the central nervous system. Apolipoprotein E transports cholesterol from astrocytes to neurons and other glial cells, regulating cell signaling in the brain. 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. 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. Data suggest that astrocytes also signal to neurons through Ca²⁺-dependent release of

glutamate Glutamic acid (symbol Glu or E; known as glutamate in its anionic form) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a Essential amino acid, non-essential nutrient for humans, meaning that ...

. Such discoveries have made astrocytes an important area of research within the field of

neuroscience Neuroscience is the scientific study of the nervous system (the brain, spinal cord, and peripheral nervous system), its functions, and its disorders. It is a multidisciplinary science that combines physiology, anatomy, molecular biology, ...

Structure

Astrocytes are a sub-type of glial cells in the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...

. They are also known as ''astrocytic glial cells.'' Star-shaped, their many processes envelop

synapses In the nervous system, a synapse is a structure that allows a neuron (or nerve cell) to pass an electrical or chemical signal to another neuron or a target effector cell. Synapses can be classified as either chemical or electrical, depending o ...

made by neurons. In humans, a single astrocyte cell can interact with up to 2 million synapses at a time. Astrocytes are classically identified using

histological Histology, also known as microscopic anatomy or microanatomy, is the branch of biology that studies the microscopic anatomy of biological tissue (biology), tissues. Histology is the microscopic counterpart to gross anatomy, which looks at large ...

analysis; many of these cells express the intermediate filament glial fibrillary acidic protein (GFAP).

Types

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

Fibrous glia

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 A capillary is a small blood vessel, from 5 to 10 micrometres in diameter, and is part of the microcirculation system. Capillaries are microvessels and the smallest blood vessels in the body. They are composed of only the tunica intima (the inn ...

walls when they are in proximity to them.

Protoplasmic glia

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.

Radial glia

The

radial glial cell Radial glial cells, or radial glial progenitor cells (RGPs), are Bipolar neuron, bipolar-shaped progenitor cells that are responsible for producing all of the neurons in the cerebral cortex. RGPs also produce certain lineages of glia, including as ...

s are disposed in planes perpendicular to the axes of ventricles. One of their processes abuts the

pia mater Pia mater ( or ),Entry "pia mater"
in
neuron migration. Müller cells of the

retina The retina (; or retinas) is the innermost, photosensitivity, light-sensitive layer of tissue (biology), tissue of the eye of most vertebrates and some Mollusca, molluscs. The optics of the eye create a focus (optics), focused two-dimensional ...

and Bergmann glia cells of the

cerebellar cortex The cerebellum (: cerebella or cerebellums; Latin for 'little brain') is a major feature of the hindbrain of all vertebrates. Although usually smaller than the cerebrum, in some animals such as the mormyrid fishes it may be as large as it or e ...

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

Early assessments of energy use in gray matter signaling suggested that 95% was attributed to neurons and 5% to astrocytes. 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. 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. Therefore "Gram-per-gram, astrocytes turn out to be as expensive as neurons".

Development

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 A neuron (American English), neurone (British English), or nerve cell, is an membrane potential#Cell excitability, excitable cell (biology), cell that fires electric signals called action potentials across a neural network (biology), neural net ...

subtypes and that of macroglial cells. Just as with neuronal cell specification, canonical signaling factors like

sonic hedgehog Sonic hedgehog protein (SHH) is a major signaling molecule of embryonic development in humans and animals, encoded by the ''SHH'' gene. This signaling molecule is key in regulating embryonic morphogenesis in all animals. SHH controls organoge ...

(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. 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 Slit homolog 1 protein is a protein that in humans is encoded by the ''SLIT1'' gene. References Further reading

* * * * * * * * * * {{protein-stub Slit proteins ...

). 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. 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

Metabolic interactions between astrocytes and neurons with major reactions

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. 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. Astrocyte endfeet processes

* 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 Glycogen is a multibranched polysaccharide of glucose that serves as a form of energy storage in animals, fungi, and bacteria. It is the main storage form of glucose in the human body. Glycogen functions as one of three regularly used forms ...

and are capable of

gluconeogenesis Gluconeogenesis (GNG) is a metabolic pathway that results in the biosynthesis of glucose from certain non-carbohydrate carbon substrates. It is a ubiquitous process, present in plants, animals, fungi, bacteria, and other microorganisms. In verte ...

. The astrocytes next to neurons in the

frontal cortex The frontal lobe is the largest of the four major lobes of the brain in mammals, and is located at the front of each cerebral hemisphere (in front of the parietal lobe and the temporal lobe). It is parted from the parietal lobe by a groove betw ...

and

hippocampus The hippocampus (: hippocampi; via Latin from Ancient Greek, Greek , 'seahorse'), also hippocampus proper, is a major component of the brain of humans and many other vertebrates. In the human brain the hippocampus, the dentate gyrus, and the ...

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. * 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. * Blood–brain barrier: The astrocyte endfeet processes encircling

s were thought to aid in the maintenance of the

, and recent research indicates that they do play a substantial role, along with the tight junctions and

basal lamina The basal lamina is a layer of extracellular matrix secreted by the epithelial cells, on which the epithelium sits. It is often incorrectly referred to as the basement membrane, though it does constitute a portion of the basement membrane. The b ...

. 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. * 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. (This has been disputed for hippocampal astrocytes.) * 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. 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. * Modulation of synaptic transmission: In the

supraoptic nucleus The supraoptic nucleus (SON) is a nucleus of magnocellular neurosecretory cells in the hypothalamus of the mammalian brain. The nucleus is situated at the base of the brain, adjacent to the optic chiasm. In humans, the SON contains about 3,000 ...

of the

hypothalamus The hypothalamus (: hypothalami; ) is a small part of the vertebrate brain that contains a number of nucleus (neuroanatomy), nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrin ...

, rapid changes in astrocyte morphology have been shown to affect heterosynaptic transmission between neurons. In the

, astrocytes suppress synaptic transmission by releasing ATP, which is

hydrolyzed Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution, elimination, and solvation reactions in which water is the nucleophile. Biological hydrolysi ...

by ectonucleotidases to yield

adenosine Adenosine (symbol A) is an organic compound that occurs widely in nature in the form of diverse derivatives. The molecule consists of an adenine attached to a ribose via a β-N9- glycosidic bond. Adenosine is one of the four nucleoside build ...

. Adenosine acts on neuronal

adenosine receptor The adenosine receptors (or P1 receptors) are a class of Purinergic receptor, purinergic G protein-coupled receptors with adenosine as the endogenous ligand (biochemistry), ligand. There are four known types of adenosine receptors in humans: Aden ...

s to inhibit synaptic transmission, thereby increasing the

dynamic range Dynamics (from Greek δυναμικός ''dynamikos'' "powerful", from δύναμις ''dynamis'' " power") or dynamic may refer to: Physics and engineering * Dynamics (mechanics), the study of forces and their effect on motion Brands and ent ...

available for LTP. * Vasomodulation: Astrocytes may serve as intermediaries in neuronal regulation of blood flow. * 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

oligodendrocyte Oligodendrocytes (), also known as oligodendroglia, are a type of neuroglia whose main function is to provide the myelin sheath to neuronal axons in the central nervous system (CNS). Myelination gives metabolic support to, and insulates the axons ...

s. 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. * Nervous system repair: Upon injury to nerve cells within the central nervous system, astrocytes fill up the space to form a

glial scar A glial scar formation (gliosis) is a reactive cellular process involving astrogliosis that occurs after injury to the central nervous system. As with scarring in other organs and tissues, the glial scar is the body's mechanism to protect and beg ...

, 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. 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. Astrocytes that have been pushed into a reactive phenotype (termed astrogliosis, defined by the upregulation of among others, GFAP and

vimentin Vimentin is a structural protein that in humans is encoded by the ''VIM'' gene. Its name comes from the Latin ''vimentum'' which refers to an array of flexible rods. Vimentin is a Intermediate filament#Type III, type III intermediate filamen ...

expression, a definition still under debate) may actually be toxic to neurons, releasing signals that can kill neurons. 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. *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. *The switch of the nervous system: Based on the evidence listed below, it has been recently conjectured in, 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. Neural detector nossenson 2013

Astrocytes are linked by

gap junction Gap junctions are membrane channels between adjacent cells that allow the direct exchange of cytoplasmic substances, such small molecules, substrates, and metabolites. Gap junctions were first described as ''close appositions'' alongside tight ...

s, creating an electrically coupled (functional) syncytium. 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. Calcium elevations are the primary known axis of activation in astrocytes, and are necessary and sufficient for some types of astrocytic glutamate release. 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. 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.

Tripartite synapse

Within the dorsal horn of the

, activated astrocytes have the ability to respond to almost all neurotransmitters and, upon activation, release a multitude of neuroactive molecules such as

, ATP,

nitric oxide Nitric oxide (nitrogen oxide, nitrogen monooxide, or nitrogen monoxide) is a colorless gas with the formula . It is one of the principal oxides of nitrogen. Nitric oxide is a free radical: it has an unpaired electron, which is sometimes den ...

(NO), and prostaglandins (PG), which in turn influences neuronal excitability. The close association between astrocytes and

presynaptic In the nervous system, a synapse is a structure that allows a neuron (or nerve cell) to pass an electrical or chemical signal to another neuron or a target effector cell. Synapses can be classified as either chemical or electrical, depending o ...

and postsynaptic terminals as well as their ability to integrate synaptic activity and release neuromodulators has been termed the tripartite synapse. 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.

Glutamatergic gliotransmission

Some specialized astrocytes mediate glutamatergic gliotransmission in the

. Such cells have been called hybrid brain cells because they exhibit both neuron-like and glial-like properties. Unlike traditional

neurons A neuron (American English), neurone (British English), or nerve cell, is an membrane potential#Cell excitability, excitable cell (biology), cell that fires electric signals called action potentials across a neural network (biology), neural net ...

, 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.

Clinical significance

Astrocytomas

Astrocytomas are

primary tumor A primary tumor is a tumor growing at the anatomical site where tumor progression began and proceeded to yield a cancerous mass. Most solid cancers develop at their primary site but may then go on to metastasize or spread to other parts of the b ...

s 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.Astrocytomas
. International RadioSurgery Association (2010). 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. They also occur more frequently in children and teens.Astrocytoma Tumors
American Association of Neurological Surgeons (August 2005). 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 Malignancy () is the tendency of a medical condition to become progressively worse; the term is most familiar as a characterization of cancer. A ''malignant'' tumor contrasts with a non-cancerous benign tumor, ''benign'' tumor in that a malig ...

. Fibrillary astrocytomas commonly occur in younger people, who often present with seizures. 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. 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

s. 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.

Neurodevelopmental disorders

Astrocytes have emerged as important participants in various

neurodevelopmental disorder Neurodevelopmental disorders are a group of mental conditions negatively affecting the development of the nervous system, which includes the brain and spinal cord. According to the American Psychiatric Association Diagnostic and Statistical Manu ...

s. This view states that astrocyte dysfunction may result in improper neural circuitry, which underlies certain psychiatric disorders such as autism spectrum disorders and

schizophrenia Schizophrenia () is a mental disorder characterized variously by hallucinations (typically, Auditory hallucination#Schizophrenia, hearing voices), delusions, thought disorder, disorganized thinking and behavior, and Reduced affect display, f ...

Chronic pain

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 The cerebral cortex, also known as the cerebral mantle, is the outer layer of neural tissue of the cerebrum of the brain in humans and other mammals. It is the largest site of Neuron, neural integration in the central nervous system, and plays ...

, 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 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. In the past,

hyperalgesia Hyperalgesia ( or ; ''hyper'' from Greek ὑπέρ (''huper'') 'over' + ''-algesia'' from Greek ἄλγος (algos) 'pain') is an abnormally increased sensitivity to pain, which may be caused by damage to nociceptors or peripheral nerves and ...

was thought to be modulated by the release of substance P and excitatory amino acids (EAA), such as

, from the presynaptic afferent nerve terminals in the spinal cord dorsal horn. Subsequent activation of

AMPA α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, better known as AMPA, is a compound that is a specific agonist for the AMPA receptor, where it mimics the effects of the neurotransmitter glutamate Glutamic acid (symbol Glu or E; kn ...

(α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid), NMDA (N-methyl-D-aspartate) and kainate subtypes of ionotropic

glutamate receptor Glutamate receptors are synaptic and non synaptic receptors located primarily on the membranes of neuronal and glial cells. Glutamate (the conjugate base of glutamic acid) is abundant in the human body, but particularly in the nervous system ...

s 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 Calcitonin gene-related peptide (CGRP) is a neuropeptide that belongs to the calcitonin family. Human CGRP consists of two Protein isoform, isoforms, CGRP alpha (α-CGRP, also known as CGRP I) and CGRP beta (β-CGRP, also known as CGRP II). α-C ...

(CGRP),

adenosine triphosphate Adenosine triphosphate (ATP) is a nucleoside triphosphate that provides energy to drive and support many processes in living cell (biology), cells, such as muscle contraction, nerve impulse propagation, and chemical synthesis. Found in all known ...

(ATP),

brain-derived neurotrophic factor Brain-derived neurotrophic factor (BDNF), or abrineurin, is a protein found in the and the periphery. that, in humans, is encoded by the ''BDNF'' gene. BDNF is a member of the neurotrophin family of growth factors, which are related to the can ...

(BDNF),

somatostatin Somatostatin, also known as growth hormone-inhibiting hormone (GHIH) or by #Nomenclature, several other names, is a peptide hormone that regulates the endocrine system and affects neurotransmission and cell proliferation via interaction with G ...

vasoactive intestinal peptide Vasoactive intestinal peptide, also known as vasoactive intestinal polypeptide or VIP, is a peptide hormone that is vasoactive in the intestine. VIP is a peptide of 28 amino acid residue (chemistry), residues that belongs to a Secretin family, glu ...

(VIP), galanin, and

vasopressin Mammalian vasopressin, also called antidiuretic hormone (ADH), arginine vasopressin (AVP) or argipressin, is a hormone synthesized from the ''AVP'' gene as a peptide prohormone in neurons in the hypothalamus, and is converted to AVP. It ...

are all synthesized and released in response to

noxious stimuli A noxious stimulus is a stimulus strong enough to threaten the body's integrity (i.e. cause damage to tissue). Noxious stimulation induces peripheral afferents responsible for transducing pain (including A-delta and C- nerve fibers, as well a ...

. 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

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

MAPK A mitogen-activated protein kinase (MAPK or MAP kinase) is a type of serine/threonine-specific protein kinases involved in directing cellular responses to a diverse array of stimuli, such as mitogens, osmotic stress, heat shock and proinflamm ...

s (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 In physiology, nociception , also nocioception; ) is the Somatosensory system, sensory nervous system's process of encoding Noxious stimulus, noxious stimuli. It deals with a series of events and processes required for an organism to receive a pai ...

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

Other clinically significant pathologies involving astrocytes include astrogliosis and astrocytopathy. Examples of these include

multiple sclerosis Multiple sclerosis (MS) is an autoimmune disease resulting in damage to myelinthe insulating covers of nerve cellsin the brain and spinal cord. As a demyelinating disease, MS disrupts the nervous system's ability to Action potential, transmit ...

, anti-AQP4+ neuromyelitis optica,

Rasmussen's encephalitis Rasmussen syndrome, also known as Rasmussen's encephalitis, is a rare progressive autoimmune Neurology, neurological disease. It is characterized by frequent and severe Focal seizure, focal seizures, progressive neurological decline, hemiparesis ( ...

, Alexander disease, and

amyotrophic lateral sclerosis Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND) or—in the United States—Lou Gehrig's disease (LGD), is a rare, Terminal illness, terminal neurodegenerative disease, neurodegenerative disorder that results i ...

. Studies have shown that astrocytes may be implied in

neurodegenerative disease A neurodegenerative disease is caused by the progressive loss of neurons, in the process known as neurodegeneration. Neuronal damage may also ultimately result in their death. Neurodegenerative diseases include amyotrophic lateral sclerosis, mul ...

s, such as

Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...

Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a neurodegenerative disease primarily of the central nervous system, affecting both motor system, motor and non-motor systems. Symptoms typically develop gradually and non-motor issues become ...

Huntington's disease Huntington's disease (HD), also known as Huntington's chorea, is an incurable neurodegenerative disease that is mostly Genetic disorder#Autosomal dominant, inherited. It typically presents as a triad of progressive psychiatric, cognitive, and ...

Stuttering Stuttering, also known as stammering, is a speech disorder characterized externally by involuntary repetitions and prolongations of sounds, syllables, words, or phrases as well as involuntary silent pauses called blocks in which the person who ...

and

, and in acute brain injuries, such as intracerebral hemorrhage and traumatic brain injury.

Gomori-positive astrocytes and brain dysfunction

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. Gomori-positive cytoplasmic granules are derived from damaged mitochondria engulfed within lysosomes. Cytoplasmic granules contain undigested remnants of mitochondrial structures. These contents include heme-linked copper and iron atoms remaining from mitochondrial enzymes. 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. 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. 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. 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.

Possible roles in pathophysiology

Astrocytes can transfer mitochondria into adjacent neurons to improve neuronal function. 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. 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. 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. 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. GP astrocytes possess high-capacity GLUT2-type glucose transporter proteins and appear to modulate the neuronal responses to glucose. 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. 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. 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. Another study showed that 100% of hippocampal astrocytes that contain FABP7 also contain FABP5. 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

A study performed in November 2010 and published March 2011, was done by a team of scientists from the

University of Rochester The University of Rochester is a private university, private research university in Rochester, New York, United States. It was founded in 1850 and moved into its current campus, next to the Genesee River in 1930. With approximately 30,000 full ...

and University of Colorado School of Medicine. They did an experiment to attempt to repair trauma to the

Central Nervous System The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...

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. One study done in

Shanghai Shanghai, Shanghainese: , Standard Chinese pronunciation: is a direct-administered municipality and the most populous urban area in China. The city is located on the Chinese shoreline on the southern estuary of the Yangtze River, with the ...

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 In neuroscience, long-term potentiation (LTP) is a persistent strengthening of synapses based on recent patterns of activity. These are patterns of synaptic activity that produce a long-lasting increase in signal transmission between two neuron ...

with the mixed culture (which is the culture that was grown from a layer of astrocytes) but not in GCM cultures. Studies have shown that astrocytes play an important function in the regulation of neural

stem cell In multicellular organisms, stem cells are undifferentiated or partially differentiated cells that can change into various types of cells and proliferate indefinitely to produce more of the same stem cell. They are the earliest type of cell ...

s. Research from the Schepens Eye Research Institute at

Harvard Harvard University is a private Ivy League research university in Cambridge, Massachusetts, United States. Founded in 1636 and named for its first benefactor, the Puritan clergyman John Harvard, it is the oldest institution of higher lear ...

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. In a study published in a 2011 issue of ''Nature Biotechnology'' a group of researchers from the University of Wisconsin reports that it has been able to direct embryonic and induced human

stem cells In multicellular organisms, stem cells are undifferentiated or partially differentiated cells that can change into various types of cells and proliferate indefinitely to produce more of the same stem cell. They are the earliest type of cell ...

to become astrocytes. A 2012 study of the effects of

marijuana Cannabis (), commonly known as marijuana (), weed, pot, and ganja, List of slang names for cannabis, among other names, is a non-chemically uniform psychoactive drug from the ''Cannabis'' plant. Native to Central or South Asia, cannabis has ...

on short-term memories found that THC activates CB1 receptors of astrocytes which cause receptors for

to be removed from the membranes of associated neurons. A 2023 study showed that astrocytes also play an active role in

. 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

There are several different ways to classify astrocytes.

Lineage and antigenic phenotype

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 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''.

Anatomical classification

*Protoplasmic: found in grey matter and have many branching processes whose end-feet envelop

. Some protoplasmic astrocytes are generated by multipotent subventricular zone progenitor cells. * 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 A stain is a discoloration that can be clearly distinguished from the surface, material, or medium it is found upon. They are caused by the chemical or physical interaction of two dissimilar materials. Accidental staining may make materials app ...

. It is now known that these granules are formed from the remnants of degenerating mitochondria engulfed within lysosomes, 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

and in the hippocampus than in other brain regions. They may have a role in regulating the response of the hypothalamus to glucose. *Fibrous: found in

white matter White matter refers to areas of the central nervous system that are mainly made up of myelinated axons, also called Nerve tract, tracts. Long thought to be passive tissue, white matter affects learning and brain functions, modulating the distr ...

and have long thin unbranched processes whose end-feet envelop

nodes of Ranvier Nodes of Ranvier ( ), also known as myelin-sheath gaps, occur along a myelinated axon where the axolemma is exposed to the extracellular space. Nodes of Ranvier are uninsulated axonal domains that are high in sodium and potassium ion channels ...

. Some fibrous astrocytes are generated by radial glia.

Transporter/receptor classification

*GluT type: these express glutamate transporters ( EAAT1/ and EAAT2/) 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. *GluR type: these express glutamate receptors (mostly mGluR and

type) and respond to synaptic release of glutamate by channel-mediated currents and IP3-dependent Ca²⁺ transients.

References

External links

Cell Centered Database – Astrocyte
*
"Astrocytes"
at Society for Neuroscience * The Department of Neuroscience at Wikiversity
NIF Search – Astrocyte
via the

Neuroscience Information Framework The Neuroscience Information Framework is a repository of global neuroscience web resources, including experimental, clinical, and translational neuroscience databases, knowledge bases, atlases, and genetic/ genomic resources and provides many aut ...

{{Authority control Central nervous system Glial cells Human cells