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: 4.28). 10/2009; 112(2):397-409. DOI: 10.1111/j.1471-4159.2009.06462.x
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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.

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Available from: Warren L May, Nov 12, 2014
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    • "Women have a higher lifetime prevalence of depression than men [3] and the duration of treatment-induced remission is shorter for women than men [2]. Also, human postmortem studies of regional brain mRNA markers in depression have identified different patterns in females vs. males [4,5]. Consequently, one strategy to reduce heterogeneity when studying depressed patients employed by several recent studies is to focus exclusively on females [6-8]. "
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    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 · 2.21 Impact Factor
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    • "Transcriptional regulators mediate a number of brain functions and behaviors that are dysregulated in MDD, including learning and memory, fear consolidation, and cognitive function (Morris et al., 1988; Ressler et al., 2002; Malkani et al., 2004). Transcriptional dysregulation has also been previously implicated in the etiology of diverse neuropsychiatric disorders such as Rett syndrome, addiction, schizophrenia, bipolar disorder, and MDD (Law et al., 2006; Monteggia and Kavalali, 2009; Goswami et al., 2010; Soria et al., 2010; Robison and Nestler, 2011). Because of its key role in central 5-HT neurotransmission and extensive evidence for its functional and structural alterations in mood disorders, along with similar alterations in rodent models of depression, the DR likely plays a key role in the pathophysiology of MDD. "
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    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.
    Frontiers in Neuroscience 10/2012; 6:135. DOI:10.3389/fnins.2012.00135 · 3.66 Impact Factor
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    • "For example, we find that females have significantly higher 5-HT 1A receptor binding than males (Arango et al. 2001), a finding replicated by our group in vivo with positron emission tomography (PET) (Parsey et al. 2002). Goswami et al. (2010) reported that mRNA concentrations of the 5-HT 1D receptor as well as transcription regulators were significantly increased in DRN laser-captured neurons of female MDD subjects compared to female control subjects, while no differences were reported in male subjects from both groups. Some postmortem studies showed greater 5-HT 1A receptor binding in the ventrolateral PFC (Arango et al. 1995; Lowther et al. 1997), while other studies did not find any changes (Stockmeier et al. 1997). "
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    ABSTRACT: The serotonergic system has been shown to be affected in a number of psychiatric illnesses in the last 50 years. A large body of work has focused on serotonin (5-HT) deficits in major depressive disorder (MDD) and suicide. A great deal has been learned about the anatomy, development, and functional organization of the 5-HT system and the alterations in this system that are present within the suicide brain. Historically, evidence for the involvement of 5-HT in suicide stemmed from findings of low cerebral spinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) in depressed suicide attempters and in the brain stems of completed suicides (Åsberg 1976; Åsberg et al. 1976; Banki et al. 1984; Carlsson et al. 1980; Mann and Malone 1997; Placidi et al. 2001; Roy et al. 1986; Träskman et al. 1981). Suicide attempters also exhibit a blunted release of prolactin in response to administration of fenfluramine, a measure of 5-HT activity (Dulchin et al. 2001; Duval et al. 2001; Malone et al. 1996; Mann et al. 1995; Pandey 1997; Weiss and Coccaro 1997). These studies provided evidence for deficits in serotonergic neurotransmission in the brain stem or serotonergic targets in the forebrain of suicidal individuals. 5-HT is produced by neurons embedded in the midline raphe nuclei in the brain stem with widespread targets that appear to be topographically organized. In this chapter, we will discuss data that shed light into the contribution of these serotonergic neurons to brain diseases such as MDD and suicide.
    The Neurobiological Basis of Suicide, Edited by Yogesh Dwivedi, 07/2012: chapter Chapter 2; CRC Press., ISBN: 9781439838815
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