Gene Expression Profiling in Postmortem Prefrontal Cortex of Major Depressive Disorder

Abstract

Investigations of the molecular mechanisms underlying major depressive disorder (MDD) have been hampered by the complexity of brain tissue and sensitivity of gene expression profiling approaches. To address these issues, we used discrete microdissections of postmortem dorsolateral prefrontal cortex (DLPFC) (area 9) and an oligonucleotide (60mer) microarray hybridization procedure that increases sensitivity without RNA amplification. Mixed-effects statistical methods were used to rigorously control for medication usage in the subset of medicated depressed subjects. These analyses yielded a rich profile of dysregulated genes. Two of the most highly dysregulated genes of interest were stresscopin, a neuropeptide involved in stress responses, and Forkhead box D3 (FOXD3), a transcription factor. Secondary cell-based analysis demonstrated that stresscopin and FoxD3 are increased in neurons of DLPFC gray matter of MDD subjects. These findings identify abnormal gene expression in a discrete region of MDD subjects and contribute to further elucidation of the molecular alterations of this complex mood disorder.

BICC1 Expression is Elevated in Depressed Subjects and Contributes to Depressive Behavior in Rodents

“…Brain tissue was collected as previously described from MDD and psychiatrically healthy matched subjects (Duric et al, 2013;Kang et al, 2007;Sibille et al, 2011). Informed consent was obtained from the next of kin for all subjects, and all procedures were approved by the University of Pittsburgh's Committee for the Oversight of Research Involving the Dead and Institutional Review Board for Biomedical Research, or by the Institutional Review Board of the University Hospitals of Cleveland.…”

The Reduction of R1, a Novel Repressor Protein for Monoamine Oxidase A, in Major Depressive Disorder

“…In vitro studies suggest that mitochondrial dysfunction and apoptotic cell death may be induced by MAO-dependent H 2 O 2 production (Kunduzova et al, 2002). Importantly, signs of cell death and oxidative damage have been observed in the brains of depressed patients Rajkowska et al, 2005;Schmidt and Duman, 2007), including patients with MDD (Duman and Monteggia, 2006;Dwivedi et al, 2009;Gawryluk et al, 2010;Kang et al, 2007). Hence, the increased expression of MAO A may participate in the apoptotic process seen in MDD, in addition to its primary monoamine-lowering activity that occurs during MDD.…”

“…A second reason why we hypothesize that decreased R1 levels occur in MDD is because lower R1 levels have been implicated in reduced cell proliferation and increased apoptotic cell death (Ou et al, 2006b), and there is evidence for the latter in MDD (Duman and Monteggia, 2006;Dwivedi et al, 2009;Gawryluk et al, 2010;Kang et al, 2007); however, R1 protein expression has not been previously evaluated in human postmortem brains of subjects with MDD. This study will constitute the initial evaluation of R1 protein levels in human postmortem brain tissue related to the molecular basis underlying the pathology of MDD.…”

Distribuição dos neurônios e campos terminais que expressam a urocortina 3 no sistema nervoso central de primata não-humano (Cebus apella).

“…A expressão do RNAm para UCN 3 foi encontrada em diversos órgãos periféricos e em poucas áreas corticais e subcorticais, tais como no hipotálamo, corpo amigdalóide e tronco encefálico (Hsu e Hsueh, 2001;Kang et al, 2007;Lewis et al, 2001) diferentemente da distribuição do CRF (Bittencourt et al, 1999;Swanson et al, 1983) e UCN 2 ).…”

“…Os autores atribuíram essa alteração da regulação de UCN 3 à possível resposta homeostática ao estresse e/ou a outras patologias associadas com a depressão (Kang et al, 2007).…”