title: 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) signaling 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 BA 10 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.
authors.affiliation: Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216-4505, USA. dharmendra_goswami@hms.harvard.edu
authors.forename: Dharmendra B
authors.initials: DB
authors.lastname: Goswami
authors.forename: Courtney S
authors.initials: CS
authors.lastname: Jernigan
authors.forename: Agata
authors.initials: A
authors.lastname: Chandran
authors.forename: Abiye H
authors.initials: AH
authors.lastname: Iyo
authors.forename: Warren L
authors.initials: WL
authors.lastname: May
authors.forename: Mark C
authors.initials: MC
authors.lastname: Austin
authors.forename: Craig A
authors.initials: CA
authors.lastname: Stockmeier
authors.forename: Beata
authors.initials: B
authors.lastname: Karolewicz
mesh_terms: D000328:Adult; D000368:Aged; D000435:Alcoholic Intoxication / Q000150:complications; D001923:Brain Chemistry / Q000502:physiology; D002102:Cadaver; D003627:Data Interpretation, Statistical; D003865:Major Depressive Disorder / Q000235:genetics*; D039721:Diagnostic and Statistical Manual of Mental Disorders; D005260:Female; D015870:Gene Expression / Q000502:physiology*; D018698:Glutamic Acid / Q000502:physiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D017397:Prefrontal Cortex / Q000378:metabolism*; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D015398:Signal Transduction / Q000502:physiology; D012907:Smoking / Q000009:adverse effects; D058570:TOR Serine-Threonine Kinases / Q000235:genetics
chemical_list: D018698:Glutamic Acid; D012313:RNA; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases