Transcriptional expression of serotonergic regulators in laser-captured microdissected dorsal raphe neurons of subjects with major depressive disorder: sex-specific differences.

Department of Psychiatry & Human Behavior, University of Mississippi Medical Center, Jackson, Mississippi, USA.
Journal of Neurochemistry (Impact Factor: 4.24). 10/2009; 112(2):397-409. DOI: 10.1111/j.1471-4159.2009.06462.x
Source: PubMed

ABSTRACT The relationship between serotonin (5-HT) and major depressive disorder (MDD) has been extensively studied but certain aspects are still ambiguous. Given the evidence that 5-HT neurotransmission is reduced in depressed subjects, it is possible that one or more of the 5-HT regulators may be altered in the dorsal raphe nucleus (DR) of depressed subjects. Candidates that regulate 5-HT synthesis and neuronal activity of 5-HT neurons include intrinsic regulators such as tryptophan hydroxylase 2, 5-HT autoreceptors, 5-HT transporter and transcription factors, as well as afferent regulators such as estrogen and brain-derived neurotrophic factor. The present study was designed to quantify mRNA concentrations of the above 5-HT regulators in an isolated population of 5-HT-containing DR neurons of MDD subjects and gender-matched psychiatrically normal control subjects. We found that mRNA concentrations of the 5-HT1D receptor and the transcription factors, NUDR and REST, were significantly increased in DR-captured neurons of female MDD subjects compared to female control subjects. No significant differences were found for the transcripts in male MDD subjects compared to male controls. This study reveals sex-specific alterations in gene expression of the pre-synaptic 5-HT1D autoreceptors and 5-HT-related transcription factors, NUDR and REST, in DR neurons of women with MDD.


Available from: Warren L May, Nov 12, 2014
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Double-stranded (ds) RNA of viral origin, a ligand for Melanoma Differentiation Associated gene 5 (MDA5) and Toll-Like Receptor 3 (TLR3), induces the TANK-Binding Kinase 1 (TBK1) -dependent phosphorylation and activation of Interferon Regulatory Factor 3 (IRF3) and the E3 ubiquitin ligase Pellino1, which are required for interferon β (IFNβ) gene transcription. Here, we report that Pellino1 interacts with the transcription factor Deformed Epidermal Autoregulatory Factor 1 (DEAF1) The interaction is independent of the E3 ligase activity of Pellino1, but weakened by the phosphorylation of Pellino1. We show that DEAF1 binds to the IFNβ promoter and to IRF3 and IRF7, that it is required for the transcription of the IFNβ gene and IFNβ secretion in MEFs infected with Sendai virus or transfected with poly(I:C). DEAF1 is also needed for TLR3-dependent IFNβ production. Taken together, our results identify DEAF1 as a novel component of the signal transduction network by which dsRNA of viral origin stimulates IFNβ production.
    Journal of Biological Chemistry 07/2013; DOI:10.1074/jbc.M113.479550 · 4.60 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: DEAF1 is a transcriptional regulator associated with autoimmune and neurological disorders and is known to bind TTCG motifs. To further ascertain preferred DEAF1 DNA ligands, we screened a random oligonucleotide library containing an "anchored" CpG motif. We identified a binding consensus that generally conformed to a repeated TTCGGG motif, with the two invariant CpG dinucleotides separated by 6-11 nucleotides. Alteration of the consensus surrounding the dual CpG dinucleotides, or cytosine methylation of a single CpG half-site, eliminated DEAF1 binding. A sequence within the Htr1a promoter that resembles the binding consensus but contains a single CpG motif was confirmed to have low affinity binding with DEAF1. A DEAF1 binding consensus was identified in the EIF4G3 promoter and ChIP assay showed endogenous DEAF1 was bound to the region. We conclude that DEAF1 preferentially binds variably spaced and unmethylated CpG-containing half-sites when they occur within an appropriate consensus.
    PLoS ONE 12/2014; 9(12):e115908. DOI:10.1371/journal.pone.0115908 · 3.53 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Depressive Disorders (DD) are a great financial and social burden. Females display 70% higher rate of depression than males and more than 30% of these patients do not respond to conventional medications. Thus medication-refractory female patients are a large, under-served, group where new biological targets for intervention are greatly needed. We used real-time quantitative polymerase chain reaction (qPCR) to evaluate mRNA gene expression from peripheral blood leukocytes for 27 genes, including immune, HPA-axis, ion channels, and growth and transcription factors. Our sample included 23 females with medication refractory DD: 13 with major depressive disorder (MDD), 10 with bipolar disorder (BPD). Our comparison group was 19 healthy, non-depressed female controls. We examined differences in mRNA expression in DD vs. controls, in MDD vs. BPD, and in patients with greater vs. lesser depression severity. DD patients showed increased expression for IL-10, IL-6, OXTR, P2RX7, P2RY1, and TRPV1. BPD patients showed increased APP, CREB1, NFKB1, NR3C1, and SPARC and decreased TNF expression. Depression severity was related to increased IL-10, P2RY1, P2RX1, and TRPV4 expression. These results support prior findings of dysregulation in immune genes, and provide preliminary evidence of dysregulation in purinergic and other ion channels in females with medication-refractory depression, and in transcription and growth factors in those with BPD. If replicated in future research examining protein levels as well as mRNA, these pathways could potentially be used to explore biological mechanisms of depression and to develop new drug targets.
    BMC Psychiatry 10/2013; 13(1):273. DOI:10.1186/1471-244X-13-273 · 2.24 Impact Factor