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The GABAergic deficit hypothesis of major depressive disorder

Molecular Psychiatry volume 16, pages 383406 (2011) | Download Citation

Abstract

Increasing evidence points to an association between major depressive disorders (MDDs) and diverse types of GABAergic deficits. In this review, we summarize clinical and preclinical evidence supporting a central and causal role of GABAergic deficits in the etiology of depressive disorders. Studies of depressed patients indicate that MDDs are accompanied by reduced brain concentration of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) and by alterations in the subunit composition of the principal receptors (GABAA receptors) mediating GABAergic inhibition. In addition, there is abundant evidence that suggests that GABA has a prominent role in the brain control of stress, the most important vulnerability factor in mood disorders. Furthermore, preclinical evidence suggests that currently used antidepressant drugs (ADs) designed to alter monoaminergic transmission and nonpharmacological therapies may ultimately act to counteract GABAergic deficits. In particular, GABAergic transmission has an important role in the control of hippocampal neurogenesis and neural maturation, which are now established as cellular substrates of most if not all antidepressant therapies. Finally, comparatively modest deficits in GABAergic transmission in GABAA receptor-deficient mice are sufficient to cause behavioral, cognitive, neuroanatomical and neuroendocrine phenotypes, as well as AD response characteristics expected of an animal model of MDD. The GABAergic hypothesis of MDD suggests that alterations in GABAergic transmission represent fundamentally important aspects of the etiological sequelae of MDDs that are reversed by monoaminergic AD action.

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Acknowledgements

We thank Byron Jones, Pam Mitchell and Casey Kilpatrick for critical reading of the manuscript. Research in the Luscher laboratory is supported by grants MH62391, MH60989 and RC1MH089111 from the National Institutes of Mental Health (NIMH), and a grant from the Pennsylvania Department of Health using Tobacco Settlement Funds. The contents of this review are solely the responsibility of the authors and do not necessarily represent the views of the NIMH or the NIH. The Pennsylvania Department of Health specifically disclaims responsibility for any analyses, interpretations or conclusions.

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Affiliations

  1. Departments of Biology, Pennsylvania State University, University Park, PA, USA

    • B Luscher
    •  & N Sahir
  2. Departments of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA, USA

    • B Luscher
    •  & Q Shen
  3. Department of Psychiatry, College of Medicine, Pennsylvania State University, Hershey, PA, USA

    • B Luscher
  4. Center for Molecular Investigation of Neurological Disorders, The Huck Institutes of the Life Sciences, Pennsylvania State University, University Park, PA, USA

    • B Luscher
    • , Q Shen
    •  & N Sahir

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The authors declare no conflict of interest.

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Correspondence to B Luscher.

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https://doi.org/10.1038/mp.2010.120