The International Journal of Neuropsychopharmacology

Research Article

Reduced level of glutamic acid decarboxylase-67 kDa in the prefrontal cortex in major depression

Beata Karolewicza1 c1, Dorota Maciaga1, Gillian O'Dwyera1, Craig A. Stockmeiera1a2, Anteneh M. Feyissaa1 and Grazyna Rajkowskaa1

a1 Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, MS, USA

a2 Department of Psychiatry, Case Western Reserve University, Cleveland, OH, USA

Abstract

Accumulating evidence suggests dysfunction of the gamma-aminobutyric acid (GABA) system in major depressive disorder (MDD). Neuroimaging studies consistently report reductions of cortical GABA in depressed patients. Our post-mortem analyses demonstrate a reduction in the density and size of GABAergic interneurons in the dorsolateral prefrontal cortex (DLPFC) in MDD. The goal of this study was to test whether the level of glutamic acid decarboxylase (GAD), the GABA synthesizing enzyme, will also be reduced in the same cortical region in MDD. Levels of GAD-65 and GAD-67 proteins were investigated by Western blotting in samples from the DLPFC (BA 9) in 13 medication-free subjects with MDD, and 13 psychiatrically healthy controls. The overall amount of GAD-67 was significantly reduced (−34%) in depressed subjects compared to matched controls. Since recent neuroimaging studies have demonstrated that antidepressants modulate GABA levels, additional experiments were performed to examine the levels of GAD in eight depressed subjects treated with antidepressant medications. Levels of GAD-67 were unchanged in these depressed subjects compared to their respective controls (n=8). The overall amounts of GAD-65 were similar in depressed subjects compared to matched controls, regardless of antidepressant medication. Reduced levels of GAD-67, which is localized to somata of GABA neurons, further support our observation of a decreased density of GABAergic neurons in the PFC in depression. It is likely that a decrease in GAD-67 accounts for the reduction in GABA levels revealed by neuroimaging studies. Moreover, our data support previous neuroimaging observations that antidepressant medication normalizes GABA deficits in depression.

(Received November 17 2008)

(Reviewed January 12 2009)

(Revised June 24 2009)

(Accepted August 05 2009)

(Online publication September 15 2009)

Correspondence:

c1 Address for correspondence: B. Karolewicz, Ph.D., University of Mississippi Medical Center, Department of Psychiatry and Human Behavior, 2500 North State Street, Jackson, MS 39216, USA. Tel.: 601-984-5896 Fax: 601-984-5899 Email: bkarolewicz@psychiatry.umsmed.edu

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