Gene expression analysis of novel genes in the prefrontal cortex of major depressive disorder subjects

Abstract

Dysregulation of the glutamatergic system has been implicated not only in the treatment of major depressive disorder (MDD), but also in the excitotoxic effects of stress and anxiety on the prefrontal cortex, which may precede the onset of a depressive episode. Our previous studies demonstrate marked deficits in prominent postsynaptic proteins involved in glutamate neurotransmission in the prefrontal cortex (PFC), Brodmann’s area 10 (BA 10) from subjects diagnosed with major depressive disorder (MDD). In the same group of subjects we have identified deficits in expression and phosphorylation level of key components of the mammalian target of rapamycin (mTOR) signalling pathway, known to regulate translation initiation. Based on our previous findings, we have postulated that glutamate-dependent dysregulation of mTOR- initiated protein synthesis in the PFC may underlie the pathology of MDD. The aim of this study was to use the NanoString nCounter System to perform analysis of genes coding for glutamate transporters, glutamate metabolizing enzymes, neurotrophic factors and other intracellular signaling markers involved in glutamate signaling that were not previously investigated by our group in the PFC BA10 from subjects with MDD. We have analyzed a total of 200 genes from 16 subjects with MDD and 16 healthy controls. These are part of the same cohort used in our previous studies. Setting our cutoff p-value ≤ 0.01, marked upregulation of genes coding for mitochondrial glutamate carrier (GC1; p=0.0015), neuropilin 1 (NRP-1; p=0.0019), glutamate receptor ionotropic N-methyl-D-aspartate-associated protein 1 (GRINA; p=0.0060), and fibroblast growth factor receptor 1 (FGFR-1; p=0.010) was identified. No significant differences in expression of the remaining 196 genes were observed between MDD subjects and controls. While upregulation of FGFR-1 has been previously shown in MDD; abnormalities in GC-1, GRINA, and NRP-1 have not been reported. Therefore, this postmortem study identifies GC1, GRINA, and NRP-1 as novel factors associated with MDD; however, future studies will be needed to address the significance of these genes in the pathophysiology of depression and antidepressant activity.

Aberrant NMDA receptor DNA methylation detected by epigenome-wide analysis of hippocampus and prefrontal cortex in major depression

“…Furthermore, GRIN2A receptor was found up-regulated in human PFC of MDD patients [31]. This is consistent with Fig.…”

Ketamine ameliorates depressive-like behaviors and immune alterations in adult rats following maternal deprivation

“…In CSF, the two-way ANOVA did not show differences in TNF-␣ levels for ketamine treatment (F (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19) (n = 5-6). *P < 0.05 vs. non-deprived + saline; # P < 0.05 vs. deprived rats treated with saline according to two-way ANOVA followed by Tukey post hoc test.…”

“…Thus, numerous studies have been conducted with the aim of better understanding the neurobiology of this disorder, as well as finding pharmacological targets with faster actions and more effectiveness [3][4][5][6][7]. The glutamatergic system is one such target of study in depression.…”

Astrocytic abnormalities and global DNA methylation patterns in depression and suicide

“…Only tissue from the left hemisphere (grey matter only) was used. These cortical regions are consistently implicated in depression [17][18][19][20] and are involved in higher order functioning such as decision-making, that is impaired in suicide 21 .…”