Bidirectional Homeostatic Regulation of a Depression-Related Brain State by Gamma-Aminobutyric Acidergic Deficits and Ketamine Treatment

Zhen Ren, Horia Pribiag, Sarah J. Jefferson, Matthew Shorey, Thomas Fuchs, David Stellwagen, Bernhard Luscher

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85 Scopus citations


Background Major depressive disorder is increasingly recognized to involve functional deficits in both gamma-aminobutyric acid (GABA)ergic and glutamatergic synaptic transmission. To elucidate the relationship between these phenotypes, we used GABAA receptor γ2 subunit heterozygous (γ2+/−) mice, which we previously characterized as a model animal with construct, face, and predictive validity for major depressive disorder. Methods To assess possible consequences of GABAergic deficits on glutamatergic transmission, we quantitated the cell surface expression of N-methyl-D-aspartate (NMDA)-type and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-type glutamate receptors and the function of synapses in the hippocampus and medial prefrontal cortex of γ2+/− mice. We also analyzed the effects of an acute dose of the experimental antidepressant ketamine on all these parameters in γ2+/− versus wild-type mice. Results Modest defects in GABAergic synaptic transmission of γ2+/− mice resulted in a strikingly prominent homeostatic-like reduction in the cell surface expression of NMDA-type and AMPA-type glutamate receptors, along with prominent functional impairment of glutamatergic synapses in the hippocampus and medial prefrontal cortex. A single subanesthetic dose of ketamine normalized glutamate receptor expression and synaptic function of γ2+/− mice to wild-type levels for a prolonged period, along with antidepressant-like behavioral consequences selectively in γ2+/− mice. The GABAergic synapses of γ2+/− mice were potentiated by ketamine in parallel but only in the medial prefrontal cortex. Conclusions Depressive-like brain states that are caused by GABAergic deficits involve a homeostatic-like reduction of glutamatergic transmission that is reversible by an acute, subanesthetic dose of ketamine, along with regionally selective potentiation of GABAergic synapses. The data merge the GABAergic and glutamatergic deficit hypotheses of major depressive disorder.

Original languageEnglish (US)
Pages (from-to)457-468
Number of pages12
JournalBiological Psychiatry
Issue number6
StatePublished - Sep 15 2016

All Science Journal Classification (ASJC) codes

  • Biological Psychiatry


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