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Roles of Glutamine Synthetase Inhibition in Epilepsy

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Abstract

Glutamine synthetase (GS, E.C. 6.3.1.2) is a ubiquitous and highly compartmentalized enzyme that is critically involved in several metabolic pathways in the brain, including the glutamine-glutamate-GABA cycle and detoxification of ammonia. GS is normally localized to the cytoplasm of most astrocytes, with elevated concentrations of the enzyme being present in perivascular endfeet and in processes close to excitatory synapses. Interestingly, an increasing number of studies have indicated that the expression, distribution, or activity of brain GS is altered in several brain disorders, including Alzheimer’s disease, schizophrenia, depression, suicidality, and mesial temporal lobe epilepsy (MTLE). Although the metabolic and functional sequelae of brain GS perturbations are not fully understood, it is likely that a deficiency in brain GS will have a significant biological impact due to the critical metabolic role of the enzyme. Furthermore, it is possible that restoration of GS in astrocytes lacking the enzyme could constitute a novel and highly specific therapy for these disorders. The goals of this review are to summarize key features of mammalian GS under normal conditions, and discuss the consequences of GS deficiency in brain disorders, specifically MTLE.

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Acknowledgments

The authors are supported by grants from the National Institutes of Health (NIH): NINDS K08 NS058674 and R01 NS070824 to TE and NIMH R01 MH095104 to KB. This work was also made possible by CTSA Grant Number UL1 RR024139 from the National Center for Advancing Translational Sciences (NCATS), a component of the National Institutes of Health (NIH), and NIH roadmap for Medical Research. The contents of the publication are solely the responsibility of the authors and do not necessarily represent the official view of NCATS or NIH.

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  1. Department of Laboratory Medicine, Yale University School of Medicine, 330 Cedar Street, P.O. Box 208035, New Haven, CT, 06520-8035, USA

    Tore Eid & Ronnie Dhaher

  2. Department of Psychiatry, Yale University School of Medicine, New Haven, CT, 06520-8035, USA

    Kevin Behar & Tih-Shih W. Lee

  3. Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, 06520-8035, USA

    Argyle V. Bumanglag

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  1. Tore Eid
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Correspondence to Tore Eid.

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Special Issue: In Honor of Leif Hertz.

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Eid, T., Behar, K., Dhaher, R. et al. Roles of Glutamine Synthetase Inhibition in Epilepsy. Neurochem Res 37, 2339–2350 (2012). https://doi.org/10.1007/s11064-012-0766-5

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