Altered Organization of GABA(A) Receptor mRNA Expression in the Depressed Suicide Brain

Abstract

Inter-relationships ordinarily exist between mRNA expression of GABA(A) subunits in the frontopolar cortex (FPC) of individuals that had died suddenly from causes other than suicide. However, these correlations were largely absent in persons that had died by suicide. In the present investigation, these findings were extended by examining GABA(A) receptor expression patterns (of controls and depressed individuals that died by suicide) in the orbital frontal cortex (OFC), hippocampus, amygdala. locus coeruleus (LC) and paraventricular nucleus (PVN), all of which have been implicated in either depression, anxiety or stress responsivity. Using QPCR analysis, we found that in controls the inter-relations between GABA(A) subunits varied across brain regions, being high in the hippocampus and amygdala, intermediate in the LC, and low in the OFC and PVN. The GABA(A) subunit inter-relations were markedly different in persons that died by suicide, being reduced in hippocampus and amygdala, stable in the LC, but more coordinated in the OFC and to some extent in the PVN. It seems that altered brain region-specific inhibitory signaling, stemming from altered GABA(A) subunit coordination, are associated with depression/suicide. Although, it is unknown whether GABA(A) subunit re-organization was specifically tied to depression, suicide, or the accompanying distress, these data show that the coordinated expression of this transcriptome does vary depending on brain region and is plastic.

Keywords: GABAA receptors; depression; human; stress; suicide.

Figure 1

Coordinated expression decreased in the hippocampus of suicides. In (A) regression graphs show examples of three significant correlated subunit pairs of controls that were not significantly correlated in suicide hippocampus shown in (B). In suicide hippocampus (lower portion of the correlation matrix; the frequency of inter-relations was diminished. In the matrix (C) all possible correlations are shown. In control brain (upper portion of the correlation matrix) thirteen subunit pairs were significantly correlated. (red indicates a statistically significant positive correlation was found, yellow indicates a non significant correlation).

Figure 2

Coordinated expression is decreased in the amygdala of suicides. In (A) the regression graphs show examples of three significantly correlated subunit pairs among controls that were not significantly correlated in suicide amygdala shown in (B). In (C) the matrix of all possible correlations are shown. In control brain upper portion of matrix eight subunit pairs were significantly correlated. In suicide hippocampus the frequency of inter-relations was diminished. (Red indicates a statistically significant positive correlation was found yellow indicates a non significant correlation).

Figure 3

Coordinated expression of GABA_A subunits was increased in the OFC of suicides. In (A) three regression graphs are shown, for control tissue, where only the α1 versus γ2 subunits are correlated (middle panel). In (B) (suicide tissue) each of these relationships were significantly related. In (C) the matrix of all possible correlations are shown. In control brain only three subunit pairs were significantly correlated (upper portion of the correlation matrix). However, the frequency of inter-relations was significantly higher in suicide brain (lower portion of the correlation matrix). (Red indicates a statistically significant positive correlation was found yellow indicates a non significant correlation while green indicates a statistically relevant negative correlation was found).

Figure 4

Coordinated expression was increased in the PVN of suicides. In (A) regression graphs show examples of three uncorrelated subunit pairs in the PVN of controls that were significantly correlated in suicide PVN shown in (B). In (C) the matrix of all possible correlations are shown. In control brain three pairs were found to be significantly correlated (upper portion of the correlation matrix). In suicide PVN the frequency of inter-relations was increased to 8. (red indicates a statistically significant positive correlation was found yellow indicates a non significant correlation).