Astrocytes play a crucial role in regulating and maintaining the extracellular chemical milieu of the central nervous system under physiological conditions. Moreover, proliferation of phenotypically altered astrocytes (a.k.a. reactive
astrogliosis) has been associated with many neurologic and
psychiatric disorders, including mesial
temporal lobe epilepsy (MTLE).
Glutamine synthetase (GS), which is found in astrocytes, is the only
enzyme known to date that is capable of converting
glutamate and
ammonia to
glutamine in the mammalian brain. This reaction is important, because a continuous supply of
glutamine is necessary for the synthesis of
glutamate and
GABA in neurons. The known stoichiometry of
glutamate transport across the astrocyte plasma membrane also suggests that rapid metabolism of intracellular
glutamate via GS is a prerequisite for efficient
glutamate clearance from the extracellular space. Several studies have indicated that the activity of GS in astrocytes is diminished in several
brain disorders, including MTLE. It has been hypothesized that the loss of GS activity in MTLE leads to increased extracellular
glutamate concentrations and epileptic
seizures. Understanding the mechanisms by which GS is regulated may lead to novel therapeutic approaches to MTLE, which is frequently refractory to
antiepileptic drugs. This review discusses several known mechanisms by which GS expression and function are influenced, from transcriptional control to
enzyme modification.