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

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 (PFC) 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 dorsolateral PFC (BA9) 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 as compared to matched controls. Since recent neuroimaging studies demonstrate that antidepressants modulate GABA levels, additional experiments were performed to examine the levels of GAD in 8 depressed subjects treated with antidepressant medications. Levels of GAD-67 were unchanged in these depressed subjects as 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.

Developmental Influence of the Serotonin Transporter on the Expression of Npas4 and GABAergic Markers: Modulation by Antidepressant Treatment

“…Interestingly, there is recent evidence that treatment with antidepressants can revert the reduction of Gad67 in human depressed subjects (Karolewicz et al, 2010), which parallels our findings. These findings suggest that antidepressant treatment can normalize the dysfunction of the GABAergic system (Luscher et al, 2011), which may lead to the increase in GABA release observed in patients (Carter and McCormack, 2009;Sanacora et al, 2002).…”

GABA interneurons mediate the rapid antidepressant-like effects of scopolamine

“…Postmortem studies have reported a reduced number of calbindin + (putative SST) interneurons and decreased expression of SST interneuron markers in the PFC (41,42), demonstrating that altered SST/GABA function is associated with depressive symptoms (43). Our prior studies indicate that scopolamine can reverse anhedonia in a chronic unpredictable stress (CUS) model of depression.…”

The role of anti-glutamic acid decarboxylase autoantibodies in mood disorders

“…Karolewicz et al [41] measured the levels of GAD 65 and GAD 67 in postmortem brain samples from the gray matter of left dorsolateral prefrontal cortex (DLPFC, Brodmann's Area 9) of MDD patients, treated and untreated with antidepressants. GAD 65 and GAD 67 were reduced in antidepressant-free MDD subjects compared to matched controls.…”

“…This reduction was not present in MDD patients medicated with antidepressants at the time of death, suggesting that GAD 65 and GAD 67 might play a role in depressive syndromes. [41] Fatemi et al [42] investigated the cerebellar levels of Reelin 410, 330 and 180 kDa, GAD 65 , and GAD 67 in subjects with BD, schizophrenia, MDD, and controls using the well-characterized Stanley Brain Consortium Collection. They found a reduction in levels of GAD 65 and GAD 67 proteins in all psychiatric subjects.…”