Mechanisms of Disease: Astrocytes in Neurodegenerative Disease

Cellular Functions of Astrocytes

We will begin by highlighting a subset of the many cellular functions of astrocytes, focusing specifically on those functions that have the most relevance to neurodegeneration (Figure 1). Other astrocytic functions, which are beyond the scope of this Review, include the regulation of cell volume, structural support, and the release of neurotransmitters other than glutamate.

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Normal Functions of Astrocytes. (1)Astrocyte functions include modulation of synaptic function via glutamate transporters, which convey glutamate from the synaptic cleft into the cell.^[1] (2)Communication between astrocytes occurs via ATP release and binding to purine receptors on adjacent astrocytes.^[14] ATP binding results in phospholipase C activation, with subsequent downstream activation of inositol trisphosphate, resulting in calcium mobilization. (3)Gap junctions contribute to an astrocyte syncytium for the exchange of small molecules and cell–cell communication.^[14] Metabolic functions include (4) the replenishment of neuronal glutamate via the glutamate–glutamine cycle, and (5) the transport of glucose from the vasculature.^[1] (6)The regulation of blood flow is modulated by astrocyte end-feet apposing blood vessels, with vasodilation being mediated through release of vasoactive substances.^[3,4] (7)Glutamate release might occur following elevations in intracellular calcium and the activation of other factors related to prostaglandins.^[12] (8)Glutamate release through hemichannels can be induced in vitro through lowering of extracellular calcium.^[13] (9)Glutamate binding to metabotropic glutamate receptors activates intracellular calcium, leading to the release of vasodilatory substances.^[4] Abbreviations: Gln, glutamine; Glu, glutamate; IP₃, inositol trisphosphate; PLC, phospholipase C.

Astrocytes are central to the catabolism of selected amino acids in the brain, as well as to the synthesis of new amino acids. The production of longer carbon backbones in the brain can only occur in astrocytes, owing to the selective localization of pyruvate carboxylase, the only brain enzyme capable of replenishing molecular intermediates for other metabolic reactions.

Astrocytes transport various nutrient and metabolic precursors to neurons via the malate–aspartate shuttle. One of the most important metabolic links between neurons and astrocytes, however, is the glutamate–glutamine shuttle. Astrocytes transport the vast majority of extracellular glutamate (especially neurotransmitter pools) and convert it to glutamine. This glutamine is shuttled back to presynaptic terminals, and is critical for the synthesis of the neurotransmitter glutamate. Astrocytes also convert glucose to lactic acid, which is subsequently taken up into neurons and converted to pyruvate for energy metabolism.^[1]

Astrocytes have an important role in the regulation of ion concentrations in the intracellular and extracellular spaces in the brain. Carbon dioxide is produced by neurons following the oxidative metabolism of pyruvate. Astrocytes regulate acid–base balance via carbonic anhydrase, which converts carbon dioxide and water to hydrogen ions and bicarbonate ions. Extracellular potassium also accumulates from neural activity,^[2] and buffering of potassium occurs through potassium channels expressed by astrocytes at synapses and at end-foot processes around capillaries.

Evidence is accumulating that astrocytes have an important function in cerebrovascular regulation. Astrocytic processes have end-feet with contact to the brain vasculature, and they envelop neuronal synapses. The relationship between neurons, astrocytes and blood vessels makes astrocytes a central element that can modulate neuronal activity and cerebral blood flow. In vitro and in vivo studies of cortical tissue indicate that synaptic release of glutamate activates metabotropic glutamate receptors on astrocytes. These receptors trigger the release of arachidonic acid metabolites,^[3] leading to a localized increase in calcium at astrocyte end-feet, which results in dilation of nearby arterioles.^[4]

Glutamate is the primary excitatory neurotransmitter in the CNS, and its activity is carefully regulated by both neuronal and glial influences. The majority of synaptic and perisynaptic glutamate regulation occurs through glutamate transporters. In addition to the tightly coupled synaptic relationship between neuronal synapses and astrocytes, astrocyte-to-astrocyte transmission through gap junctions, as well as paracrine release of ATP, might modulate synaptic biology.

Regulation of Glutamate Transport. Glutamate transport is a sodium- and potassium-coupled process that is capable of concentrating intracellular glutamate more than 10,000-fold compared with the extracellular environment. The glutamate transporters GLAST and GLT1 (EAAT1 and EAAT2 in humans; also known as EAA1 and EAA2) are localized primarily on astrocyte membranes.^[5,6,7,8] Antisense knockdown studies showed that these two glial transporters are responsible for over 80% of glutamate uptake in the brain,^[9] an observation that was later confirmed in GLT1 (Slc1a2)-null mice.^[10]

Release of Glutamate. Although glutamate is the primary neuronal excitatory neurotransmitter in the brain, evidence also exists for an astrocytic role in glutamate release. In vitro preparations have demonstrated astrocyte-specific glutamate release via exocytosis.^[11,12] Certain conditions, such as low levels of extracellular calcium, can trigger glutamate release through a separate mechanism, namely hemichannels—a single cell's contribution to a gap junction.^[13] These findings are intriguing in that they suggest an additional layer of fine-tuning of the perisynaptic environment modulated by astrocytes.

Propagation of Glutamatergic Transmission via the Astrocyte Network. Current evidence indicates that propagation of glutamate transmission through the astrocyte syncytium occurs through two prominent calcium-mediated mechanisms: one involving gap junctions and the other involving paracrine release of ATP. Activation of metabotropic glutamate receptors on astrocytes following neuronal release of glutamate results in the activation of an inositol trisphosphate (IP₃) pathway, which induces calcium release from intracellular stores. This calcium can then be transferred to the adjacent astrocyte through connexin 43 (Cx43) gap junctions, thereby producing a calcium wave through an astrocyte syncytium. IP₃ also activates ATP release through Cx43 hemichannels. This ATP release acts in a paracrine fashion, activating purine receptors on adjacent astrocytes. This activation results in IP₃ production, more ATP release and intracellular calcium mobilization through a feed-forward mechanism.^[14]

Nat Clin Pract Neurol. 2006;2(12):679-689. © 2006 Nature Publishing Group

Cite this: Mechanisms of Disease: Astrocytes in Neurodegenerative Disease - Medscape - Dec 01, 2006.