Global Brain Gene Expression Analysis Links Glutamatergic and GABAergic Alterations to Suicide and Major Depression

Abstract

BackgroundMost 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 FindingsWe 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/SignificanceThe 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.

Biological Alterations in Depression

“…Consistent with previous findings, expression of genes involved in signal transmission of glutamate and GABA were found to be dysregulated in depressed patients (Choudary et al, 2005) and in suicide victims with and without depression (Sequeira et al, 2009). Alteration in genes regulating oligodendrocyte function (Sequeira & Turecki, 2006) and cell-cell communication (Sequeira et al, 2009) were altered in MDD, suggesting impairment in brain circuitry. Notably, reduced oligodendrocyte expression and neuronal changes in amygdala were detected in both depressed individuals and in rodents exposed to unpredictable chronic mild stress (Sibille et al, 2009), indicating a connection between stress response and neural circuitry.…”

“…Similarly, dysregulation of fibroblast growth factor genes (FGF1, FGF2, FGFR2, and, FGF3) were detected in cortical regions of depressed patients, irrespective of previous antidepressant treatment (Evans et al, 2004). Consistent with previous findings, expression of genes involved in signal transmission of glutamate and GABA were found to be dysregulated in depressed patients (Choudary et al, 2005) and in suicide victims with and without depression (Sequeira et al, 2009). Alteration in genes regulating oligodendrocyte function (Sequeira & Turecki, 2006) and cell-cell communication (Sequeira et al, 2009) were altered in MDD, suggesting impairment in brain circuitry.…”

Effect of newly synthesized 1,2,4-triazino[5,6-b]indole-3-thione derivatives on olfactory bulbectomy induced depression in rats

“…Current treatment for depression includes drugs such as selective serotonin reuptake inhibitors, tricyclic antidepressants and monoamine oxidase inhibitors. They are effective and tolerated well but noncompliance due to slow action, low response, and plethora of side effects are generally observed [10][11][12][13][14][15][16][17] . Also they inhibit sexual behavior [18] .…”

Bi-phasic regulation of glycogen content in astrocytes via Cav-1/PTEN/PI3K/AKT/GSK-3β pathway by fluoxetine

“…At the same time treatment with antidepressants increases GFAP levels (Barley et al 2009). Expression of another astroglial marker, the calcium-binding protein S100β has been reduced in the ventral prefrontal cortex of depressed suicide victims (Klempan et al 2009). Several other astroglial markers, such as aquaporin 4, astroglial connexins, astroglial plasmalemmal glutamate transporters and glutamine synthetase are all down-regulated in mood disorders (Rajkowska et al 2013;Barley et al 2009;Bernard et al 2011;Sequeira et al 2009).…”

“…Expression of another astroglial marker, the calcium-binding protein S100β has been reduced in the ventral prefrontal cortex of depressed suicide victims (Klempan et al 2009). Several other astroglial markers, such as aquaporin 4, astroglial connexins, astroglial plasmalemmal glutamate transporters and glutamine synthetase are all down-regulated in mood disorders (Rajkowska et al 2013;Barley et al 2009;Bernard et al 2011;Sequeira et al 2009). Reduced number of astrocytes and of their packing density was detected throughout the fronto-limbic areas of the brain, including the orbito-frontal area, and anterior cingulate, prefrontal, entorhinal and subgenual cortices, as well as the amygdala (Rajkowska et al 2013;Verkhratsky et al 2014;Popoli et al 2011;Sanacora et al 2013).…”