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Altered GABA function in Major Depression

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Synaptic Stress and Pathogenesis of Neuropsychiatric Disorders

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Abstract

Disrupted information transfer and processing at gamma-aminobutyric acid (GABA) and glutamate synapses, especially in corticolimbic circuits, has been proposed as a critical component of the pathophysiology of mood disorders. Here we review evidence of the primary pathology from human postmortem brains, supported by imaging studies in living subjects, for alterations in pyramidal excitatory neurons, GABA inhibitory neurons, and supporting glia, including oligodendrocytes and astrocytes. The data suggest combinatorial changes in most investigated components, converge on putative functional changes at glutamate and GABA synapses, and indicate that a subset of GABA neurons, which express specific cellular markers (calbindin, somatostatin, neuropeptide Y) and target distal dendrites of pyramidal neurons, may be more selectively and robustly affected in major depression. Pathologies in this subset of GABA neurons display a continuum of changes across brain disorders, may significantly contribute to deregulated GABA-containing tripartite synapses providing dendritic inhibition, and have implications for corticolimbic information processing in major depression and other brain disorders sharing similar pathologies.

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Abbreviations

ABAT:

4-Aminobutyrate aminotransferase

ACC:

Anterior cingulate cortex

ALDH1L1:

Aldehyde hydrogenase 1 family, member L1

BA:

Brodmann area

BDNF:

Brain-derived neurotrophic factor

CB:

Calbindin

CCK:

Cholecystokinin

CORT:

Cortistatin

CR:

Calretinin

dlPFC:

Dorsal lateral prefrontal cortex

EAAT1:

Excitatory amino acid transporter1 glutamate clearance transporter 1

EAAT2:

Excitatory amino acid transporter1glutamate clearance transporter 2

GABA:

Gamma-aminobutyric acid

GABAAR:

GABA A receptor

GABABR:

GABA B receptor

GABA-T:

GABA transaminase

GABBR1:

GABA B receptor 1

GABBR2:

GABA B receptor 2

GAD:

Glutamic acid decarboxylase

GAT:

GABA transporter

GFAP:

Glial fibrillary acidic protein

GLS:

Glutaminase

GLUL:

Glutamate ammonia ligase

GS:

Glutamine synthetase

1H MRS:

Proton magnetic resonance spectroscopy

NPY:

Neuropeptide Y

OFC:

Orbital frontal cortex

PFC:

Prefrontal cortex

PV:

Parvalbumin

qPCR:

Quantitative polymerase chain reaction

sgACC:

Subgenual anterior cingulate cortex

SNAT3:

Astrocytic system N transporter

SNAT1/SNAT2:

System A transporters

SST:

Somatostatin

TRKB:

Tropomyosin related kinase B

VGAT:

Vesicular GABA transporter

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Acknowledgements

The authors have no disclosure. This work was supported by National Institute of Mental Health (NIMH) MH084060 (ES) and MH077159 (ES) grants. The funding agency had no role in the study design, data collection and analysis, decision to publish, and preparation of the manuscript. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIMH or the National Institutes of Health.

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Authors and Affiliations

  1. Department of Psychiatry, University of Pittsburgh, Bridgeside Point II, Suite 231, 450 Technology Drive, 15219, Pittsburgh, PA, USA

    Beverly French, Marianne L. Seney & Etienne Sibille

  2. Center for Neuroscience, University of Pittsburgh, Bridgeside Point II, Suite 231, 450 Technology Drive, 15219, Pittsburgh, PA, USA

    Etienne Sibille

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  1. Beverly French
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  2. Marianne L. Seney
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  3. Etienne Sibille
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Correspondence to Etienne Sibille .

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Editors and Affiliations

  1. Department of Pharmacological and Biomolecular Sciences, University of Milano, Milano, Italy

    Maurizio Popoli

  2. Department of Psychology, University of South Florida, Tampa, Florida, USA

    David Diamond

  3. Psychiatry Depression Research Program, Yale School of Medicine, New Haven, Connecticut, USA

    Gerard Sanacora

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French, B., Seney, M., Sibille, E. (2014). Altered GABA function in Major Depression. In: Popoli, M., Diamond, D., Sanacora, G. (eds) Synaptic Stress and Pathogenesis of Neuropsychiatric Disorders. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-1056-4_13

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