Astrocytes (from Ancient Greek , , "star" and , , "cavity", "cell"), also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord. They perform many functions, including biochemical control of endothelial cells that form the blood–brain barrier, provision of nutrients to the nervous tissue, maintenance of extracellular ion balance, regulation of cerebral blood flow, and a role in the repair and scarring process of the brain and spinal cord following infection and traumatic injuries. 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. Such discoveries have made astrocytes an important area of research within the field of neuroscience.
Structure
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 can interact with up to two million synapses at a time. Astrocytes are classically identified histologically; many of these cells express glial fibrillary acidic protein (GFAP), a type III intermediate filament protein.
Types Types of astrocytes in the central nervous system include fibrous (in white matter), protoplasmic (in grey matter), and radial glial cells.
Fibrous astrocytes The fibrous astrocytes are usually located within white matter, have relatively few organelles, and exhibit long unbranched cellular processes. This type often has astrocyte endfeet processes that physically connect the cells to the outside of capillary walls when they are in proximity to them.
Protoplasmic astrocytes The protoplasmic astrocytes 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 glial cells 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 grey matter. Radial glia are mostly present during development, playing a role in neuron migration. Müller cells of the retina and Bergmann glia cells of the cerebellar cortex represent an exception, being present still during adulthood. When in proximity to the pia mater, all three forms of astrocytes send out processes to form the pia-glial membrane.
Energy use Early assessments of energy use in grey 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 subtypes and that of macroglial cells. 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. 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:
Dorsally located VA1 astrocytes, derived from p1 domain, express PAX6 and reelin. Ventrally located VA3 astrocytes, derived from p3, express NKX6.1 and SLIT1. 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
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.Kolb, Brian and Whishaw, Ian Q. (2008) Fundamentals of Human Neuropsychology. Worth Publishers. 6th ed. 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.
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. 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 endothelial cells were thought to aid in the maintenance of the blood–brain barrier, and recent research indicates that they do play a substantial role, along with the tight junctions and basal lamina. 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. Trace metal homeostasis: Astrocytes are the principal regulators of trace metal homeostasis in the central nervous system. They serve as the main storage and distribution sites for copper, manganese, zinc and iron, protecting neurons from metal-induced toxicity while supplying these essential cofactors. Astrocytes accumulate copper efficiently via the high-affinity transporter CTR1 and store it bound to glutathione and metallothioneins. They export copper via the copper-transporting ATPase ATP7A, thereby supplying copper to neighbouring neurons. Astrocytes are the main storage site for manganese in the brain, accumulating roughly 50 times more Mn²⁺ than neurons. They rapidly take up excess zinc through zinc transporters, shielding neurons from zinc toxicity. Astrocytes also participate in brain iron homeostasis by uptake via DMT1 and storage in ferritin. Dysregulation of astrocyte-mediated metal homeostasis is implicated in several neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and Wilson's disease. 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. 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. 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 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.