Astrocytic regulation of glutamate homeostasis in epilepsy

Authors

  • Douglas A. Coulter,

    Corresponding author
    1. Department of Pediatrics, University of Pennsylvania School of Medicine and the Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
    2. Department of Neuroscience, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
    • Children's Hospital of Philadelphia, Abramson Research Center Room 409D, 3615 Civic Center Blvd., Philadelphia, PA 19104-4318, USA
    Search for more papers by this author
    • Douglas A. Coulter and Tore Eid contributed equally to this work.

  • Tore Eid

    Corresponding author
    1. Department of Laboratory Medicine, Yale University School of Medicine and the Clinical Chemistry Laboratory, Yale-New Haven Hospital, New Haven, Connecticut
    2. Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut
    • Department of Laboratory Medicine, Yale University School of Medicine, P.O. Box 208035, New Haven, CT 06520-8035, USA
    Search for more papers by this author
    • The contents of the publication are solely the responsibility of the authors and do not necessarily represent the official view of NCATS or NIH.


Abstract

Astrocytes play a critical role in regulation of extracellular neurotransmitter levels in the central nervous system. This function is particularly prominent for the excitatory amino acid glutamate, with estimates that 80–90% of extracellular glutamate uptake in brain is through astrocytic glutamate transporters. This uptake has significance both in regulation of the potential toxic accumulation of extracellular glutamate and in normal resupply of inhibitory and excitatory synapses with neurotransmitter. This resupply of neurotransmitter is accomplished by astroglial uptake of glutamate, transformation of glutamate to glutamine by the astrocytic enzyme glutamine synthetase (GS), and shuttling of glutamine back to excitatory and inhibitory neurons via specialized transporters. Once in neurons, glutamine is enzymatically converted back to glutamate, which is utilized for synaptic transmission, either directly, or following decarboxylation to γ-aminobutyric acid. Many neurologic and psychiatric conditions, particularly epilepsy, are accompanied by the development of reactive gliosis, a pathology characterized by anatomical and biochemical plasticity in astrocytes, accompanied by proliferation of these cells. Among the biochemical changes evident in reactive astrocytes is a downregulation of several of the important regulators of the glutamine–glutamate cycle, including GS, and possibly also glutamate transporters. This downregulation may have significance in contributing both to the aberrant excitability and to the altered neuropathology characterizing epilepsy. In the present review, we provide an overview of the normal function of astrocytes in regulating extracellular glutamate homeostasis, neurotransmitter supply, and excitotoxicity. We further discuss the potential role reactive gliosis may play in the pathophysiology of epilepsy. © 2012 Wiley Periodicals, Inc.

Ancillary