Dopamine Receptor Gene Expression in Human Amygdaloid Nuclei: Elevated D4 Receptor mRNA in Major Depression

Previous findings from this laboratory demonstrating changes in dopamine (DA) transporter and D2 receptors in the amygdaloid complex of subjects with major depression indicate that disruption of dopamine neurotransmission to the amygdala may contribute to behavioral symptoms associated with depression. Quantitative real-time RT-PCR was used to investigate the regional distribution of gene expression of DA receptors in the human amygdala. In addition, relative levels of mRNA of DA receptors in the basal amygdaloid nucleus were measured postmortem in subjects with major depression and normal control subjects. All five subtypes of DA receptor mRNA were detected in all amygdaloid subnuclei, although D1, D2, and D4 receptor mRNAs were more abundant than D3 and D5 mRNAs by an order of magnitude. The highest level of D1 mRNA was found in the central nucleus, whereas D2 mRNA was the most abundant in the basal nucleus. Levels of D4 mRNA were highest in the basal and central nuclei. In the basal nucleus, amounts of D4, but not D1 or D2, mRNAs were significantly higher in subjects with major depression as compared to control subjects. These findings demonstrate that the D1, D2 and D4 receptors are the major subtypes of DA receptors in the human amygdala. Elevated DA receptor gene expression in depressive subjects further implicates altered dopaminergic transmission in the amygdala in depression

Low Gene Expression of Bone Morphogenetic Protein 7 in Brainstem Astrocytes in Major Depression

The noradrenergic locus coeruleus (LC) is the principal source of brain norepinephrine, a neurotransmitter thought to play a major role in the pathology of major depressive disorder (MDD) and in the therapeutic action of many antidepressant drugs. The goal of this study was to identify potential mediators of brain noradrenergic dysfunction in MDD. Bone morphogenetic protein 7 (BMP7), a member of the transforming growth factor-β superfamily, is a critical mediator of noradrenergic neuron differentiation during development and has neurotrophic and neuroprotective effects on mature catecholaminergic neurons. Real-time PCR of reversed transcribed RNA isolated from homogenates of LC tissue from 12 matched pairs of MDD subjects and psychiatrically normal control subjects revealed low levels of BMP7 gene expression in MDD. No differences in gene expression levels of other members of the BMP family were observed in the LC, and BMP7 gene expression was normal in the prefrontal cortex and amygdala in MDD subjects. Laser capture microdissection of noradrenergic neurons, astrocytes, and oligodendrocytes from the LC revealed that BMP7 gene expression was highest in LC astrocytes relative to the other cell types, and that the MDD-associated reduction in BMP7 gene expression was limited to astrocytes. Rats exposed to chronic social defeat exhibited a similar reduction in BMP7 gene expression in the LC. BMP7 has unique developmental and trophic actions on catecholamine neurons and these findings suggest that reduced astrocyte support for pontine LC neurons may contribute to pathology of brain noradrenergic neurons in MDD

Prevalence and cardiometabolic associations of the glucocorticoid receptor gene polymorphisms N363S and Bcl1 in obese and non-obese black and white Mississippians

AbstrAct ObJEctIVE: Polymorphisms (sNP) in the glucocorticoid receptor (Gr) gene can alter sensitivity to glucocorticoids. Previous studies of the N363s and BclI sNP in the Gr gene have shown a metabolic syndrome phenotype in mostly non-African populations. the obesity phenotype of African Americans (AA) seems to be more severe than that of caucasians. DEsIGN: We aimed to assess the prevalence of N363s and BclI in obese and non-obese caucasian (n=26) and African (n=23) Mississippians (age: 23-63 years) to investigate associations with body composition (body mass index/bMI, waist-to-hip ratio), metabolic parameters (salivary cortisol, fasting glucose and insulin, hemoglobin A1c, fructosamine, HOMA-Ir index), and psychological stress perception (blood pressure/bP, perceived stress scale/Pss). rEsULts: All subjects were homozygous for wildtype N363N. BclI polymorphism genotype frequencies among the 23 AA were: homozygous cc (57%), GG (4%), and heterozygous cG (39%), and among the 26 white women: homozygous cc (35%), GG (19%), and heterozygous cG (46%). Linear and logistic regression analyses including a parsimonious model identified bMI as a statistically significant parameter between the two ethnic groups (bMI was 3.13 kg/m 2 higher in AA). Within the AA group, bMI, waist-to-hip ratio, log (HOMA-Ir), Pss scores, bP, and hyperlipidemia showed no statistically significant relationships for the BclI polymorphism. Pss scores were 15.2 for AA vs. 14.7 for white women (normal mean: 14.7 vs. 12.8). cONcLUsION: black Mississippians HORMONES 2012, 11(2):166-17

Microarray Analysis of Gene Expression in the Noradrenergic Locus Coeruleus in Major Depression

Previous studies have demonstrated specific biochemical abnormalities in the noradrenergic locus coeruleus (LC) that are strongly associated with major depressive disorder (MDD). Here, we studied the LC of 4 pairs of MDD and matched control subjects by gene expression microarray analysis in an effort to accelerate the discovery of pathobiological abnormalities of these cells in MDD. Among matching criteria, pH values of control (6.71±0.06) and MDD (6.66±0.12) subjects were closely matched. Gene expression profiling using whole human genome microarrays (Agilent) revealed statistically significant changes in approximately 50 transcripts in the LC of depressive subjects. Quantitative real-time PCR (qPCR) was used to analyze transcripts identified by microarray anlayses. In initial studies of 11 of these transcripts that demonstrated a \u3e2-fold change in microarrays, only 3 transcripts were confirmed by qQPCR in a larger sample of 11-12 pairs of MDD and matched control subjects. Amounts of bone morphogenetic factor-7 (BMP7; p=0.001) and potassium channel subfamily K, member 7 (KCNK7; p=0.049) mRNAs were significantly lower in MDD subjects compared to control subjects (~2-fold difference). In contrast, neurolysin mRNA levels were significantly higher (~3-fold; p=0.03) in MDD than in control subjects. BMP7 is a member of the TGF-β superfamily and has neuroprotective and neurotrophic effects on catecholaminergic neurons. The KCNK family of potassium channels contribute to the excitability of neurons. Neurolysin is a zinc-dependent metallopeptidase involved in neuropeptide metabolism. The present study is the first report of these novel gene expression abnormalities in the LC of MDD subjects. These findings enhance our understanding of the pathobiology of MDD and may represent novel targets for pharmacological management of depression