Evidence for Transcriptional Factor Dysregulation in the Dorsal Raphe Nucleus of Patients with Major Depressive Disorder

Abstract

Extensive evidence implicates dysfunction in serotonin (5-HT) signaling in the etiology of major depressive disorder (MDD). Dorsal raphe nucleus (DR) is a major source of serotonin in the brain, and previous studies have reported within it alterations in 5-HT-related gene expression, protein levels, receptor binding, and morphological organization in mood disorders. In the present study, we utilized in situ hybridization-guided laser capture microdissection to harvest tissue samples from the middle-caudal subregion of the human DR post-mortem from MDD patients and from psychiatrically normal comparison subjects. Extracted RNA was prepared for gene expression profiling, and subsequent confirmation of select targets with quantitative real-time PCR. Our data indicate expression changes in functional gene families that regulate: (1) cellular stress and energy balance, (2) intracellular signaling and transcriptional regulation, and (3) cell proliferation and connectivity. The greatest changes in expression were observed among transcriptional regulators, including downregulation in the expression of TOB1, EGR1, and NR4A2 and their downstream targets. Previous studies have implicated these gene products in the regulation of functional domains impacted by MDD, including cognitive function, affective regulation, and emotional memory formation. These observations indicate altered function of several transcriptional regulators and their downstream targets, which may lead to the dysregulation of multiple cellular functions that contribute to the pathophysiology of MDD. Future studies will require single cell analyses in the DR to determine potential impact of these changes on its cellular functions and related circuits.

LSD1 modulates stress-evoked transcription of immediate early genes and emotional behavior

“…Chronic stress results in long-lasting chromatin modifications that increase the repression of plasticity-related genes (2-4). In particular, egr1 has been reported to be downregulated in mice stressed by chronic social defeat and in postmortem brains of depressed human subjects, suggesting a pathogenic role for this down-regulation (4,31). In this regard, it is conceivable that repeated LSD1 up-and neuroLSD1 downregulation in response to chronic stress could induce H3K4 hypomethylation at the egr1 promoter (Fig.…”

Antidepressant-like Effects of Cortical Deep Brain Stimulation Coincide With Pro-neuroplastic Adaptations of Serotonin Systems

“…Whether and how chronic regimens of vmPFC DBS induce neuroplasticity in the 5-HT system is not known. Because previous studies have indicated that depression and suicide in humans (15-18) and depressive-like symptoms in animals (19-21) are accompanied by maladaptive plasticity in the 5-HT system, we hypothesized that stable neuroplastic changes in the 5-HT system may coincide with the antidepressant-like effect of chronic vmPFC DBS.…”

GATA1: a novel target for gene therapy in major depressive disorder

“…GATA1: a new transcriptional repressor of synaptic genes associated with depression Although brain imaging studies and postmortem analyses has provided much valuable information about major depression, the molecular determinants of the pathogenesis of major depressive disorder are still unknown. In the past decade, comprehensive analyses of the molecular mechanisms involved in major depression have been performed, largely consisting of high throughput analysis on postmortem brain tissues from patients with major depression (Sibille et al 2004;Kang et al 2007Kang et al , 2012Tochigi et al 2008;Kerman et al 2012;Goswami et al 2013;Medina et al 2013). Major depression is a heterogeneous disease caused by the complex interaction of genes and environmental factors.…”