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Do astrocytes connect and chemically communicate with other astrocytes?

Do astrocytes connect and chemically communicate with other astrocytes?


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I am building a novel model of neural tissue for the purposes of Machine Learning and am currently trying to unpick the functions of the astroglia.

The literature suggests that astrocytes ensheath synapses, providing them with structural support, given that the synapse is an oily droplet between two neuron 'tentacles' this makes sense, performs caretaker functions at synapses it ensheaths with regard to neurotransmitters and, via its perivascular feet, provides resources from nearby blood vessels.

The literature goes on to suggest that the astrocyte may play a role in some neurological disorders if the ionic 'effects' from one set of perivascular feet, namely one set of synapses, 'leaks' across an internal chemical barrier within said astrocyte, to spread the 'effect' to another set of perhaps unrelated synapses. I can see how this could influence and cause unrelated learning, which may be a hallmark of some neurological disorders, one of which the paper suggests is schizophrenia and its patterns of unearned and irregular learning.

I can appreciate how some form of localized learning or whole- or partial-pathway learning, as opposed to pure individual neuron-level learning, would certainly be beneficial to a learning network in speeding up learning.

Do astrocytes connect to astrocytes and if so how and what chemical messaging is present there?

I apologize that I am not a neurochemist only a software developer with a background in electronics and while I can follow some of the chemistry, I am interested in the functional purpose of these biological components. Nature only had chemistry to work with when these mechanisms evolved but, as an aside, if it had had access to electronics and software, one supposes the neural tissue would have been far easier for us to comprehend.


Astrocyte‐to‐astrocyte contact and a positive feedback loop of growth factor signaling regulate astrocyte maturation

(29 April 2019)

by Jiwen Li, Rana R. Khankan, Christine Caneda, Marlesa I. Godoy, Michael S. Haney, Mitchell C. Krawczyk, Michael C. Bassik, Steven A. Sloan, Ye Zhang Published 'Glia'

This appears to give me the details I required.

Astrocyte maturation appears to be accelerated due to chemical signalling from astrocytes in their vicinity, but astrocytes do not 'signal', as understood as a network learning characteristic, to each other.

Thank you for your assistance.


Glial Cells

Glial cells, neuroglial cells, or glia are no longer considered to have a purely structural role within the central nervous system they have also been found to regulate nerve firing rates, brain plasticity, and immune responses. These numerous small cells that lack axons and/or dendrites have been the subject of significant research, but we are still only scratching the surface of many of their roles. Glial cells exist in the central nervous system (CNS) and the peripheral nervous system some glial cell types can even move across the barrier between the CNS and PNS.


History of Glial cells

Glial cells make up the other brain cells. They are a diverse group of cells that are versatile in their range of functions.

Glial cells were first discovered in 1838 by Robert Remak. He discovered Schwann cells (named after Theodor Schwann, who confirmed Remak&rsquos discovery), which are a type of glial cell that covers the neuron&rsquos long axon. After this initial breakthrough, numerous other glial cells were uncovered, from star-shaped astrocytes, small microglia and multi-pronged oligodendrocytes.

However, all these cells, despite their diversity, were relegated to the mere status of &ldquoglue&rdquo, the Greek origin of the word &ldquoglia&rdquo. Neuroscientists of the early 20 th century thought that glia did nothing more than support the neurons in their functions.


Neurons

Four major types of neurons transmit signals through the body via specialized structures such as dendrites, axons, and synapses.

Learning Objectives

Describe the functions of the structural components of a neuron

Key Takeaways

Key Points

  • Dendrites are the tree-like structures in neurons that extend away from the cell body to receive messages from other neurons at synapses not all neurons have dendrites.
  • Synapses enable the dendrites from a single neuron to interact and receive signals from many other neurons.
  • Axons are tube-like structures that send signals to other neurons, muscles, or organs not all neurons have axons.
  • Neurons are divided into four major types: unipolar, bipolar, multipolar, and pseudounipolar.
  • Unipolar neurons have only one structure extending from the soma bipolar neurons have one axon and one dendrite extending from the soma.
  • Multipolar neurons contain one axon and many dendrites pseudounipolar neurons have a single structure that extends from the soma, which later branches into two distinct structures.

Key Terms

  • dendrite: branched projections of a neuron that conduct the impulses received from other neural cells to the cell body
  • axon: long slender projection of a nerve cell that conducts nerve impulses away from the cell body to other neurons, muscles, and organs
  • synapse: the junction between the terminal of a neuron and either another neuron or a muscle or gland cell, over which nerve impulses pass

Neurons

The nervous system of the common laboratory fly, Drosophila melanogaster, contains around 100,000 neurons, the same number as a lobster. This number compares to 75 million in the mouse and 300 million in the octopus. A human brain contains around 86 billion neurons. Despite these very different numbers, the nervous systems of these animals control many of the same behaviors, from basic reflexes to more complicated behaviors such as finding food and courting mates. The ability of neurons to communicate with each other, as well as with other types of cells, underlies all of these behaviors.

Most neurons share the same cellular components. But neurons are also highly specialized: different types of neurons have different sizes and shapes that relate to their functional roles.

Parts of a Neuron

Each neuron has a cell body (or soma) that contains a nucleus, smooth and rough endoplasmic reticulum, Golgi apparatus, mitochondria, and other cellular components. Neurons also contain unique structures, relative to most cells, which are required for receiving and sending the electrical signals that make neuronal communication possible. Dendrites are tree-like structures that extend away from the cell body to receive messages from other neurons at specialized junctions called synapses. While some neurons have no dendrites, other types of neurons have multiple dendrites. Dendrites can have small protrusions called dendritic spines, which further increase surface area for possible synaptic connections.

Cellular structure of neurons: Neurons contain organelles common to many other cells, such as a nucleus and mitochondria. They also have more specialized structures, including dendrites and axons.

Once a signal is received by the dendrite, it then travels passively to the cell body. The cell body contains a specialized structure, the axon hillock, that integrates signals from multiple synapses and serves as a junction between the cell body and an axon: a tube-like structure that propagates the integrated signal to specialized endings called axon terminals. These terminals, in turn, synapse on other neurons, muscles, or target organs. Chemicals released at axon terminals allow signals to be communicated to these other cells. Neurons usually have one or two axons, but some neurons, like amacrine cells in the retina, do not contain any axons. Some axons are covered with myelin, which acts as an insulator to minimize dissipation of the electrical signal as it travels down the axon, greatly increasing the speed on conduction. This insulation is important as the axon from a human motor neuron can be as long as a meter: from the base of the spine to the toes. The myelin sheath is not actually part of the neuron. Myelin is produced by glial cells. Along these types of axons, there are periodic gaps in the myelin sheath. These gaps, called “nodes of Ranvier,” are sites where the signal is “recharged” as it travels along the axon.

It is important to note that a single neuron does not act alone. Neuronal communication depends on the connections that neurons make with one another (as well as with other cells, such as muscle cells). Dendrites from a single neuron may receive synaptic contact from many other neurons. For example, dendrites from a Purkinje cell in the cerebellum are thought to receive contact from as many as 200,000 other neurons.

Types of Neurons

There are different types of neurons the functional role of a given neuron is intimately dependent on its structure. There is an amazing diversity of neuron shapes and sizes found in different parts of the nervous system (and across species).

Neuron diversity: There is great diversity in the size and shape of neurons throughout the nervous system. Examples include (a) a pyramidal cell from the cerebral cortex, (b) a Purkinje cell from the cerebellar cortex, and (c) olfactory cells from the olfactory epithelium and olfactory bulb.

While there are many defined neuron cell subtypes, neurons are broadly divided into four basic types: unipolar, bipolar, multipolar, and pseudounipolar. Unipolar neurons have only one structure that extends away from the soma. These neurons are not found in vertebrates, but are found in insects where they stimulate muscles or glands. A bipolar neuron has one axon and one dendrite extending from the soma. An example of a bipolar neuron is a retinal bipolar cell, which receives signals from photoreceptor cells that are sensitive to light and transmits these signals to ganglion cells that carry the signal to the brain. Multipolar neurons are the most common type of neuron. Each multipolar neuron contains one axon and multiple dendrites. Multipolar neurons can be found in the central nervous system (brain and spinal cord). The Purkinje cell, a multipolar neuron in the cerebellum, has many branching dendrites, but only one axon. Pseudounipolar cells share characteristics with both unipolar and bipolar cells. A pseudounipolar cell has a single structure that extends from the soma (like a unipolar cell), which later branches into two distinct structures (like a bipolar cell). Most sensory neurons are pseudounipolar and have an axon that branches into two extensions: one connected to dendrites that receives sensory information and another that transmits this information to the spinal cord.

Types of Neurons: Neurons are broadly divided into four main types based on the number and placement of axons: (1) unipolar, (2) bipolar, (3) multipolar, and (4) pseudounipolar.

The seven types of glia have specific functions that play a role in supporting neuron function.

Learning Objectives

Describe the specific roles that the seven types of glia play in the nervous systems

Key Takeaways

Key Points

  • Glia guide developing neurons to their destinations, buffer harmful ions and chemicals, and build the myelin sheaths around axons.
  • In the CNS astrocytes provide nutrients to neurons, give synapses structural support, and block toxic substances from entering the brain satellite glia provide nutrients and structural support for neurons in the PNS.
  • Microglia scavenge and degrade dead cells, protecting the brain from invading microorganisms.
  • Oligodendrocytes form myelin sheaths around axons in the CNS Schwann cell forms myelin sheaths around axons in the PNS.
  • Radial glia serve as bridges for developing neurons as they migrate to their end destinations.
  • Ependymal cells line fluid-filled ventricles of the brain and central canal of the spinal cord which produce cerebrospinal fluid.

Key Terms

  • satellite glia: glial cell that provides nutrients for neurons in the PNS
  • radial glia: glial cell that serves as a bridge for developing neurons as they move to their end destinations
  • astrocyte: a neuroglial cell, in the shape of a star, in the brain

While glia (or glial cells ) are often thought of as the supporting cast of the nervous system, the number of glial cells in the brain actually outnumbers the number of neurons by a factor of ten. Neurons would be unable to function without the vital roles that are fulfilled by these glial cells. Glia guide developing neurons to their destinations, buffer ions and chemicals that would otherwise harm neurons, and provide myelin sheaths around axons. Scientists have recently discovered that they also play a role in responding to nerve activity and modulating communication between nerve cells. When glia do not function properly, the result can be disastrous most brain tumors are caused by mutations in glia.

Types of Glia

There are several different types of glia with different functions. Astrocytes make contact with both capillaries and neurons in the CNS. They provide nutrients and other substances to neurons, regulate the concentrations of ions and chemicals in the extracellular fluid, and provide structural support for synapses. Astrocytes also form the blood-brain barrier: a structure that blocks entrance of toxic substances into the brain. They have been shown, through calcium-imaging experiments, to become active in response to nerve activity, transmit calcium waves between astrocytes, and modulate the activity of surrounding synapses. Satellite glia provide nutrients and structural support for neurons in the PNS. Microglia scavenge and degrade dead cells, protecting the brain from invading microorganisms. Oligodendrocytes form myelin sheaths around axons in the CNS. One axon can be myelinated by several oligodendrocytes one oligodendrocyte can provide myelin for multiple neurons. This is distinctive from the PNS where a single Schwann cell provides myelin for only one axon as the entire Schwann cell surrounds the axon. Radial glia serve as bridges for developing neurons as they migrate to their end destinations. Ependymal cells line fluid-filled ventricles of the brain and the central canal of the spinal cord. They are involved in the production of cerebrospinal fluid, which serves as a cushion for the brain, moves the fluid between the spinal cord and the brain, and is a component for the choroid plexus.

Images of glial cells: (a) Astrocytes and (b) oligodendrocytes are glial cells of the central nervous system.

Glial cells: Glial cells support neurons and maintain their environment. Glial cells of the (a) central nervous system include oligodendrocytes, astrocytes, ependymal cells, and microglial cells. Oligodendrocytes form the myelin sheath around axons. Astrocytes provide nutrients to neurons, maintain their extracellular environment, and provide structural support. Microglia scavenge pathogens and dead cells. Ependymal cells produce cerebrospinal fluid that cushions the neurons. Glial cells of the (b) peripheral nervous system include Schwann cells, which form the myelin sheath, and satellite cells, which provide nutrients and structural support to neurons.


A Window into the Brain Demonstrates the Importance of Astrocytes

Did you ever wish you could peek inside someone's brain and see what was going on in there? In research reported in this issue of PLoS Biology, Hajime Hirase and his colleagues at Rutgers University have done just that by focusing their microscope on the brains of living rats in order to examine how certain cells called astrocytes function in vivo. ​ vivo.

In the longstanding quest to understand how the brain works, scientists have focused on neurons. Neurons conduct action potentials, electrical signals that transmit information in the nervous system. But the brain also contains several other types of cells called glia. (Glia is derived from the Latin for “glue” these cells were thought to “hold it all together.”) One type of glial cell, the astrocyte (named for its starlike shape), is the most populous cell in the brain and forms an intimate association with neurons and their synapses. It was thought that these cells played a supporting role in the brain, ensuring the proper chemical environment for synapses.

Recent research, however, has suggested that astrocytes and other glial cells may play a more significant role. When examining astrocytes cultured in the lab, scientists have observed behavior suggesting that astrocytes can communicate with neurons. Though astrocytes cannot propagate electrical signals like neurons do, they can sense the transmission of such signals at the synapse between two neurons. Furthermore, astrocytes are able to propagate a different kind of signal, a chemical signal based on the release of calcium ions. Calcium signaling is a mechanism of chemical signaling that has been observed in many other cell types. The exact properties of neuron𠄺strocyte communication, however, are not clear because different preparations of these tissues have yielded different results. It has also not been established that this type of communication occurs in the living brain.

To explore such questions, Hirase and colleagues have taken the next step by investigating the calcium signaling properties of astrocytes in the brains of living rats. To accomplish this feat, the researchers used a combination of two technologies. They monitored calcium signaling using a fluorescent dye called Fluo-4, which fluoresces in response to calcium ions. Then they used a special type of microscope called a two-photon laser scanning microscope to visualize the dye. Since this type of microscope uses a lower energy laser, it can image the dye in living tissue without causing harm.

The researchers applied the dye to the brains of anesthetized rats, washed out the excess dye that had not penetrated into cells, and then imaged the tissue under the microscope. They first confirmed that they indeed were examining astrocytes and noticed that cells displayed a moderate level of baseline calcium signaling activity. They then used a drug called bicuculline to stimulate neurons and observed a significant increase in the calcium signaling activity of the astrocytes. Because bicuculline only affects neurons, this implies that the astrocytes are responding to the activity of the neurons. The researchers also found that neighboring astrocytes often also displayed coordinated calcium signaling activity, suggesting that the communication among astrocytes is facilitated by increased neuronal activity.

This research confirms the complexity of astrocyte signaling functions in the living brain and demonstrates that astrocytes play far more than a supporting role in brain function. It also establishes an important experimental system for scientists seeking to understand how these distinct elements of the brain—neurons and astrocytes—work together. Though this research makes it clear that signaling exists both among astrocytes and between neurons and astrocytes, scientists have yet to understand the effect of this signaling. Some possibilities include regulation of synapse formation, modification of synaptic strength, or more complicated roles in information processing resulting from the coordination of neuronal activity. Future research using this and other systems will help reveal these functions.


Usage of astrocyte and astrocyte-derived molecules as therapeutic targets

As a result, all of the described neuroprotective and neurodeleterious molecules, as well as their upstream and downstream factors, represent potential therapeutic targets (Fig. 3 and Table 1). However, both astrocytes and astrocyte-derived molecules can only act as targets for particular subtypes, specific damage regions, and certain stages of TBI. Therefore, therapeutic strategies must focus on the enhancement of neuroprotective effects and blockage of the neurodeleterious effects of the different factors under specific conditions.

Potential therapeutic targets regarding astrocyte-derived molecules following TBI. Following TBI, damaged cells release danger signals. And stressed intermediate filaments networks within astrocytes activate ion influx through the mechanosensitive ion channel, resulting in the further release of danger signals. These signals serve to activate neuroglia and induce a robust sterile immune reaction and other secondary TBI pathogenesis. Reactive astrocytes secrete a wide range of factors that affect neurogenesis, synaptogenesis and synaptic stability, and angiogenesis, which may represent the therapeutic targets. Modulating the maladaptive microenvironment caused by neuroinflammation, excitotoxicity and oxidative stress post-TBI is also a considerable therapeutic strategy. ANG-1, angiopoietin-1 CCL, chemokine (C-C motif) ligand CXCL, chemokine (C-X-C motif) ligand GFAP, glial fibrillary acidic protein HMGB1, high mobility group protein B1 HSP, heat shock proteins HSPGs, heparan sulfate proteoglycans IFN, interferon IGFBP-6, insulin-like growth factor binding protein 6 IL, interleukin MMP, matrix metalloprotein PACAP, pituitary adenylate cyclase-activating peptide SHH, sonic hedgehog SPARC, secreted protein acidic and rich in cysteine STAT3, signal transducer and activator of transcription-3 TBI, traumatic brain injury TGF-β, transforming growth factor-β TNF, tumor necrosis factor TSP, thrombospondin VEGF, vascular endothelial growth factor

Besides targeting astrocyte-derived molecules, stimulating the function of astrocyte-related receptors is also promising for the restoration of neuronal plasticity and reconstruction. Some astrocyte-derived molecules such as S1P and ETs also act as ligands of astrocytic receptors, and the probable therapeutic drugs are shown in the Table 1. Other receptors such as Toll-like receptors [127], purinergic receptor [227], glutamate receptor [228], hormone receptor [10, 229], and cannabinoid receptor [230] have also attracted widespread attention. Although we previously mentioned that MK-801, one of the glutamate receptor antagonists, had been shown to enhance synaptic integrity and improve cognitive outcome in the experimental study but regrettably, clinical trials concerning the glutamate receptor antagonists have been widely carried out but failed to provide a statistically significant benefit for TBI patients [231]. According to Ikonomidou et al., the failure could be attributed to the attenuation of synaptic transmission, which impedes neuronal survival [228].

Modulating the maladaptive microenvironment post-TBI is also a considerable therapeutic strategy [140,141,142]. Relevantly, agents for reducing the glutamate excitotoxicity by enhancing glutamate transporters such as parawexin 1 and certain β-lactam antibiotics could be of therapeutic benefit [232, 233]. Other potential therapeutic mediators include agents for the restoration of ionic and water balance by targeting Na + /H + transporters, Na + /K + /2Cl − cotransporters, or Na + /Ca2 + exchangers such as fluorenyl drugs [234, 235] and agents that promote neuronal survival and function such as recombinant neurotrophins or peptidomimetics [9]. Agents that alter the lesion environment by modulating inflammatory responses such as minocycline and etanercept have also been proposed as potential candidates for neuroprotection [144, 171].

We have previously reviewed the advance of stem cell treatment for TBI, which has not reached a general success in clinic application [86]. Given the vital roles of astrocyte-secreted factors in the neurogenesis and neural differentiation, a combination of stem cell treatment and astrocytic functions may present a novel therapeutic strategy. Besides, non-coding RNAs also hold therapeutic potential as astrocytes express various non-coding RNAs, which in turn control astrocytic functions [236,237,238]. And hypertonic saline has been found to elicit neuroprotection by regulating the expression of non-coding RNAs [239].


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Astrocytes process synaptic information

Astrocytes were classically considered as simple supportive cells for neurons without a significant role in information processing by the nervous system. However, considerable amounts of evidence obtained by several groups during the past years demonstrated the existence of a bidirectional communication between astrocytes and neurons, which prompted a re-examination of the role of astrocytes in the physiology of the nervous system. While neurons base their excitability on electrical signals generated across the membrane, astrocytes base their cellular excitability on variations of the Ca 2+ concentration in the cytosol. This article discusses our current knowledge of the properties of the synaptically evoked astrocyte Ca 2+ signal, which reveals that astrocytes display integrative properties for synaptic information processing. Astrocytes respond selectively to different axon pathways, discriminate between the activity of different synapses and their Ca 2+ signal is non-linearly modulated by the simultaneous activity of different synaptic inputs. Furthermore, this Ca 2+ signal modulation depends on astrocyte cellular intrinsic properties and is bidirectionally regulated by the level of synaptic activity. Finally, astrocyte Ca 2+ elevations can trigger the release of gliotransmitters, which modulate neuronal activity as well as synaptic transmission and plasticity, hence granting the bidirectional communication with neurons. Consequently, astrocytes can be considered as cellular elements involved in information processing by the nervous system.


Do astrocytes connect and chemically communicate with other astrocytes? - Biology

Microglia are resident immune cells of the brain, which derive from a different cell lineage to all other cells in the brain. They are highly motile cells, constantly patrolling the brain parenchyma.

Astrocytes are the largest cell component of the brain and develop from a common progenitor along with neurons and oligodendrocytes. They tile the entire brain and do not migrate during normal physiology. These two cell types are important for normal mammalian brain development and respond rapidly to disease, infection, and trauma.

Microglia and astrocytes interact via contact-dependent and secreted factors to modulate their function during normal health and in disease. Microglia can drive reactivity in astrocytes via the release of specific cytokines, while astrocytes can drive dysfunction in microglia by withholding cholesterol.

Many tools exist to manipulate both microglia and astrocytes, however, complete removal of astrocytes is currently impossible as this results in death.

scRNASeq experiments must be both adequately powered and take into account possible artifacts as a result of subsampling when disseminating results. Ideally, cluster-specific differentially expressed genes should be validated using visualization methods (in situ hybridization or spatial transcriptomic approaches) and functional assays.

Caution should be taken in the nomenclature of different ‘activation’ states of both microglia and astrocytes. While no method is perfect, the field needs to clearly state what constitutes a subset of cells: biologically relevant and functionally characterized descriptions will be the most beneficial.

Microglia–astrocyte interactions represent a delicate balance affecting neural cell functions in health and disease. Tightly controlled to maintain homeostasis during physiological conditions, rapid and prolonged departures during disease, infection, and following trauma drive multiple outcomes: both beneficial and detrimental. Recent sequencing studies at the bulk and single-cell level in humans and rodents provide new insight into microglia–astrocyte communication in homeostasis and disease. However, the complex changing ways these two cell types functionally interact has been a barrier to understanding disease initiation, progression, and disease mechanisms. Single cell sequencing is providing new insights however, many questions remain. Here, we discuss how to bridge transcriptional states to specific functions so we can develop therapies to mediate negative effects of altered microglia–astrocyte interactions.


Contents

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. [9] Astrocytes are classically identified using histological analysis many of these cells express the intermediate filament glial fibrillary acidic protein (GFAP). [10] Several forms of astrocytes exist in the central nervous system including fibrous (in white matter), protoplasmic (in grey matter), and radial. The fibrous glia are usually located within white matter, have relatively few organelles, and exhibit long unbranched cellular processes. This type often has astrocytic endfoot processes that physically connect the cells to the outside of capillary walls when they are in proximity to them. 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. 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.

Development Edit

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. [11] 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. [12] 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) and intermediate white-matter located VA2 astrocyte, derived from the p2 domain, which express PAX6, NKX6.1, reelin and SLIT1. [13] 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.

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. [15] 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. [16]

  • 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. [17]
  • 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. [18]
  • Blood–brain barrier: The astrocyte end-feet encircling endothelial cells were thought to aid in the maintenance of the blood–brain barrier, but recent research indicates that they do not play a substantial role instead, it is the tight junctions and basal lamina of the cerebral endothelial cells that play the most substantial role in maintaining the barrier. [19] 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. [20][21]
  • Transmitter uptake and release: Astrocytes express plasma membrane transporters such as glutamate transporters for several neurotransmitters, including glutamate, ATP, and GABA. More recently, astrocytes were shown to release glutamate or ATP in a vesicular, Ca 2+ -dependent manner. [22] (This has been disputed for hippocampal astrocytes.) [23]
  • 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. [24] 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. [25]
  • 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. [26] 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. [27]
  • Vasomodulation: Astrocytes may serve as intermediaries in neuronal regulation of blood flow. [28]
  • 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. [29]
  • 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. [30] 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. [30] Astrocytes that have been pushed into a reactive phenotype (termed astrogliosis, defined by upregulation of GFAP expression, a definition still under debate) may actually be toxic to neurons, releasing signals that can kill neurons. [31] Much work, however, remains to elucidate their role in nervous system injury.
  • Long-term potentiation: Scientists debate whether astrocytes integrate learning and memory in the hippocampus. Recently it has been shown that engrafting human glial progenitor cell in the nascent mice brains will cause the cells to differentiate into astrocytes. After differentiation these cells increase LTP and improve memory performance in the mice. [32]
  • 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. [33]
  • The switch of the nervous system: Based on the evidence listed below, it has been recently conjectured in, [34] 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.
Evidence supporting the switch and lossy capacitor role of glia as suggested in [34] [35]
Evidence type Description References
Calcium evidence Calcium waves appear only if a certain concentration of neurotransmitter is exceeded [36] [37] [38]
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. [39] [40]

Astrocytes are linked by gap junctions, creating an electrically coupled (functional) syncytium. [44] 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 Ca 2+ 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. [45] Calcium elevations are the primary known axis of activation in astrocytes, and are necessary and sufficient for some types of astrocytic glutamate release. [46] 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 Ca 2+ ions yields a localized raise in the cytosolic concentration of Ca 2+ ions. [47] Moreover, cytosolic Ca 2+ accumulation is independent of every intracellular calcium flux and depends on the Ca 2+ exchange across the membrane, cytosolic calcium diffusion, geometry of the cell, extracellular calcium perturbation, and initial concentrations. [47]

Tripartite synapse Edit

Within the dorsal horn of the spinal cord, activated astrocytes have the ability to respond to almost all neurotransmitters [48] 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. [16] Synaptic modulation by astrocytes takes place because of this three-part association.

Astrocytomas Edit

Astrocytomas are primary intracranial tumors 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 and/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. [49]

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. [49] They also occur more frequently in children and teens. [50]

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. [50]

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. [49]

Glioblastoma multiforme 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. [49]

Neurodevelopmental disorders Edit

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. [51] [6]

Chronic pain Edit

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 [52] 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. [48] [53] [54] 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 Edit

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 Ca 2+ 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 Edit

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. [55] Studies have shown that astrocytes may be implied in neurodegenerative diseases, such as Alzheimer's disease, [56] [57] Parkinson's disease, [58] Huntington's disease, Stuttering [59] and amyotrophic lateral sclerosis, [60] and in acute brain injuries, such as intracerebral hemorrhage [61] and traumatic brain injury. [62]

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. [63]

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. [64]

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. [65]

In a study published in a 2011 issue of Nature Biotechnology [66] 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 [67] 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.

There are several different ways to classify astrocytes.

Lineage and antigenic phenotype Edit

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