Function

Astrocytes share a common ECS with neurons, and virtually every neuron in the brain has a large percentage of its membrane immediately adjacent to astrocyte membrane. This situation lends itself to a role in regulating the ionic and/or chemical stability of extracellular fluid, which is necessary for normal neuronal function. In this capacity, it is true that astrocytes function to maintain constant ionic concentrations in the extracellular space by buffering K + and H + , as well as by removing neurotransmitters. The membrane of astrocytes contains many transport and exchange mechanisms that allow the movement of ions into astrocytes. Astrocytes are the ideal cell type to buffer K+ ions. K+ accumulates extracellularly after neuronal activity, with the degree of activity determining the degree of K+ elevation. It is thought that a single action potential can raise K+ by as much as 1 mM in localized areas. After intense activity, [K + ]o can rise from a baseline level of 3 mM to about 12 mM, the so-called ceiling level. This ceiling level for [K + ]o is only breached with spreading depression and under pathological conditions such as trauma or ischemia, where concentrations of 60 mM or more may be recorded. There is some controversy as to how extracellular K+ is removed or "buffered" during neural activity, but likely candidates include K + channels, Na+ K+ ATPase, and anion transporters such as the Na + K + 2Cl~ cotransporter. Once K + enters astrocytes, it can be dispersed via gap junctions to distant astrocytes and then released back into the ECS as levels return to normal (ultimately, of course, the neurons that released the K+ in the first place must reaccumulate what was lost; see Fig. 1). Extracellular pH also changes with neural activity, and astrocytes have a unique transporter, the Na+HCO^ cotranspor-ter, that helps to regulate this important ion level.

Astrocytic membranes contain neurotransmitter transporters. During neuronal activity synaptic neurotransmitters would rapidly build up if they were not sequestered intracellularly or metabolized

Figure 1 Schematic representation of mechanisms of K+ uptake in astrocytes. K+ released by active neurons is actively accumulated by astrocytes in three ways. The sodium pump and an anion transporter both take up K+. The sodium pump relies directly on the availability of ATP, whereas the anion transporter is indirectly powered by the energy stored in the transmembrane Na+ gradient. The presence of channels for Cl" and K+ allow Donnan forces to produce KCl influx. These mechanisms, along with K+ spatial buffering (see text), prevent [K+]o from exceeding ~12 mM. Increases in [K+]i are seen during neural activity as [K+]o increases.

Figure 1 Schematic representation of mechanisms of K+ uptake in astrocytes. K+ released by active neurons is actively accumulated by astrocytes in three ways. The sodium pump and an anion transporter both take up K+. The sodium pump relies directly on the availability of ATP, whereas the anion transporter is indirectly powered by the energy stored in the transmembrane Na+ gradient. The presence of channels for Cl" and K+ allow Donnan forces to produce KCl influx. These mechanisms, along with K+ spatial buffering (see text), prevent [K+]o from exceeding ~12 mM. Increases in [K+]i are seen during neural activity as [K+]o increases.

extracellularly. The most common excitatory CNS neurotransmitter is glutamate. Astrocytes take up ~90% of the glutamate released at synapses via two specific glutamate transporters called GLT1 and GLAST. The energy for this transport is provided by the transmembrane Na+ gradient (see Fig. 2). Once inside the astrocyte the glutamate is converted to glutamine by the astrocyte-specific enzyme glutamine synthetase, resulting in the dephosphorylation of one molecule of ATP. The glutamine is shuttled out of the astrocyte and into the neuron by the glutamine transport protein, where it is converted back into glutamate by the enzyme glutaminase. Similar mechanisms exist for the uptake of the major inhibitory CNS neurotransmitter, GABA.

A major function of astrocytes is as an energy store. The full importance of this function is just being realized. Astrocytes are the only cells in the CNS that store glycogen, and as such astrocytes are the only cells in the CNS with energy stores. Glycogen is formed from glucose within astrocytes via the intermediary compounds glucose 6-phosphate, glucose 1-phos-phate, and UDP-glucose in a reaction requiring ATP. Once glucose enters astrocytes it is immediately phosphorylated to glucose 6-phosphate, but the lack of the enzyme glucose-6-phosphatase, which converts glucose 6-phosphate to glucose, determines that glucose is not transported out of astrocytes. Glycogen is broken down to glucose by action of the enzyme glycogen phosphorylase. Thus, there is equilibrium between glucose and glycogen. In periods of high glucose the equilibrium favors the formation of glycogen (glycogenesis), and during periods of low glucose the equilibrium favors the breakdown of glycogen to glucose (glycogenolysis). It has been proposed that astrocytic glycogen can act as an energy source for neural elements in both gray and white matter during periods of energy deprivation.

Figure 2 Scheme showing how astrocytes are involved in glutamate metabolism and uptake. Only astrocytes contain the enzyme glutamine synthetase, which converts glutamate to glutamine in an ATP-requiring reaction. Glutamine is transported to nearby presynaptic terminals, where it is converted to glutamate for synaptic release. Finally, the released glutamate is recaptured by astrocytes via a high-affinity glutamate uptake system. Although glutamate transporters are present in neurons, astrocytes are the most active in removing glutamate (see text). In the absence of the normal transmembrane Na+ gradient maintained by the ATP-dependent Na+ pump, the glutamate transporter ceases to remove glutamate and can run in reverse so that it pumps glutamate into the ECS.

Figure 2 Scheme showing how astrocytes are involved in glutamate metabolism and uptake. Only astrocytes contain the enzyme glutamine synthetase, which converts glutamate to glutamine in an ATP-requiring reaction. Glutamine is transported to nearby presynaptic terminals, where it is converted to glutamate for synaptic release. Finally, the released glutamate is recaptured by astrocytes via a high-affinity glutamate uptake system. Although glutamate transporters are present in neurons, astrocytes are the most active in removing glutamate (see text). In the absence of the normal transmembrane Na+ gradient maintained by the ATP-dependent Na+ pump, the glutamate transporter ceases to remove glutamate and can run in reverse so that it pumps glutamate into the ECS.

Astrocytic glycogen is broken down to lactate, which is easily shuttled out of the astrocyte via the monocar-boxylate transporter MCT1 and into the neuron-axon via the monocarboxylate transporter MCT2, where it is converted to pyruvate and incorporated into the citric acid cycle to yield ATP (see Fig. 3). Neurons in gray matter and axons in white matter are sustained by lactate as well as by glucose.

drocytes. The nature of astrocyte maturation seems to indicate that two separate pathways can produce the same cell, and although there are regional differences between astrocyte morphology, it is not known whether this is as a result of the maturation phase.

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