Global brain gene expression analysis links glutamatergic and GABAergic alterations to suicide and major depression

Abstract

Background: Most studies investigating the neurobiology of depression and suicide have focused on the serotonergic system. While it seems clear that serotonergic alterations play a role in the pathogenesis of these major public health problems, dysfunction in additional neurotransmitter systems and other molecular alterations may also be implicated. Microarray expression studies are excellent screening tools to generate hypotheses about additional molecular processes that may be at play. In this study we investigated brain regions that are known to be implicated in the neurobiology of suicide and major depression are likely to represent valid global molecular alterations.

Methodology/principal findings: We performed gene expression analysis using the HG-U133AB chipset in 17 cortical and subcortical brain regions from suicides with and without major depression and controls. Total mRNA for microarray analysis was obtained from 663 brain samples isolated from 39 male subjects, including 26 suicide cases and 13 controls diagnosed by means of psychological autopsies. Independent brain samples from 34 subjects and animal studies were used to control for the potential confounding effects of comorbidity with alcohol. Using a Gene Ontology analysis as our starting point, we identified molecular pathways that may be involved in depression and suicide, and performed follow-up analyses on these possible targets. Methodology included gene expression measures from microarrays, Gene Score Resampling for global ontological profiling, and semi-quantitative RT-PCR. We observed the highest number of suicide specific alterations in prefrontal cortical areas and hippocampus. Our results revealed alterations of synaptic neurotransmission and intracellular signaling. Among these, Glutamatergic (GLU) and GABAergic related genes were globally altered. Semi-quantitative RT-PCR results investigating expression of GLU and GABA receptor subunit genes were consistent with microarray data.

Conclusions/significance: The observed results represent the first overview of global expression changes in brains of suicide victims with and without major depression and suggest a global brain alteration of GLU and GABA receptor subunit genes in these conditions.

Figure 1. Pie charts representing the distribution of the total number of differentially expressed genes in (A) prefrontal cortical areas and in (B) other cortical and subcortical brain areas.

The number of chips per group that passed quality control assessment is also given.

Figure 2. Clustered image map (CIM) of the hierarchical cluster analysis of the distribution pattern of ErmineJ calculated P-values of the 20 top overrepresented ontologies across all the regions studied.

Both ontological categories and the regions were clustered. The color and intensity indicate level of significance: red spectrum colors indicate very highly significant gene ontologies (0.001), yellow colors indicate highly significant gene ontologies (0.01) and white colors represent no significance.

Figure 3. Clustered image map (CIM) of the hierarchical cluster analysis of the GABAergic differentially expressed subunit genes across the 17 regions investigated.

The color and intensity indicate direction and level of change: blue spectrum colors indicate down-regulated expression, while red spectrum colors indicate up-regulated expression.

Figure 4. Clustered image map (CIM) of the hierarchical cluster analysis of the glutamatergic system differentially expressed genes across the 17 regions investigated.

The color and intensity indicate direction and level of change: blue spectrum colors indicate down-regulated expression, while red spectrum colors indicate.