Gender differences in brain development and in the prevalence of neuropsychiatric disorders such as depression have been reported. Gender differences in human brain might be related to patterns of gene expression. Microarray technology is one useful method for investigation of gene expression in brain. We investigated gene expression, cell types, and regional expression patterns of differentially expressed sex chromosome genes in brain. We profiled gene expression in male and female dorsolateral prefrontal cortex, anterior cingulate cortex, and cerebellum using the Affymetrix oligonucleotide microarray platform. Differentially expressed genes between males and females on the Y chromosome (DBY, SMCY, UTY, RPS4Y, and USP9Y) and X chromosome (XIST) were confirmed using real-time PCR measurements. In situ hybridization confirmed the differential expression of gender-specific genes and neuronal expression of XIST, RPS4Y, SMCY, and UTY in three brain regions examined. The XIST gene, which silences gene expression on regions of the X chromosome, is expressed in a subset of neurons. Since a subset of neurons express gender-specific genes, neural subpopulations may exhibit a subtle sexual dimorphism at the level of differences in gene regulation and function. The distinctive pattern of neuronal expression of XIST, RPS4Y, SMCY, and UTY and other sex chromosome genes in neuronal subpopulations may possibly contribute to gender differences in prevalence noted for some neuropsychiatric disorders. Studies of the protein expression of these sexchromosome-linked genes in brain tissue are required to address the functional consequences of the observed gene expression differences.
Between 1997 and 2002, 48 data sets from the hippocampus were produced on samples from the Stanley Neuropathology Consortium. From these data sets, 224 total measures were available from the various subdivisions of the hippocampus. An integrative analysis of these measures was performed using a multivariate, nonparametric analysis of variance (ANOVA). ANOVA with correction for multiple comparisons indicated that parvalbumin-containing cells in CA2 were reduced in schizophrenia and bipolar disorder. In addition, reelin protein in the molecular layer of the dentate gyrus was decreased in schizophrenia, bipolar disorder, and depression at the trend level of statistical significance (P ¼ 0.065). These results strongly suggest a dysfunction of inhibitory GABA-ergic interneurons in severe mental illness. Without correction for multiple comparisons, 31 measures were abnormal in at least one disease, whereas 11 measures would be expected to appear abnormal by chance. Abnormal molecules included measures of synaptic density or neuronal plasticity (reelin, SNAP-25, BDNF, Complexin I and II), as well as parvalbumin, tyrosine receptor kinase A, glucocorticoid receptors, glutamate NR1 receptor subunits, serotonin 5HT2 A and 5HT1 B receptors, and dopamine D 5 receptors.
The distribution of mRNA coding for the D2 dopamine receptor was studied in the rat brain by in situ hybridization. A cDNA probe corresponding to the putative third cytosolic loop and sixth and seventh transmembrane domains of the rat D2 receptor was used to generate an 35S-labeled riboprobe to hybridize to D2 receptor mRNA. D2 mRNA was found both in dopamine projection fields and in regions associated with dopamine-containing cell bodies, suggesting both postsynaptic and presynaptic autoreceptor localization. Highest concentrations of D2 mRNA were found in neostriatum, olfactory tubercle, substantia nigra, ventral tegmental area, and the nucleus accumbens. This distribution is consistent with those reported with D2 receptor autoradiography.The dopamine systems of the brain are well-studied, consisting of two major circuits and several local networks (1-3). The most extensive of the dopamine systems are the nigrostriatal circuit and the mesocorticolimbic system. These are of central importance in both regulation of motor control and modulation of emotional tone (4-6). Dysfunction of the nigrostriatal system, for example, has been implicated in a number of motor disturbances, especially Parkinson disease. Similarly, the mesocorticolimbic system has been postulated to be disturbed in some psychiatric conditions, most notably schizophrenia.The receptor for dopamine has been resolved into two physiologically distinct subtypes, referred to as D1 and D2 (7). These subtypes were proposed to explain differences in coupling to adenylate cyclase; the D1 receptor is considered to be stimulatory for this enzyme (8, 9), whereas the D2 receptor is either inhibitory or unlinked (10, 11). It has become apparent that these two dopamine receptor subtypes are distinct, having unique pharmacological profiles, biochemical characteristics, neuroanatomical distributions, and apparent molecular weights (7). Thus far, the determination of the neuroanatomical distribution of the dopamine receptors has been limited to pharmacological binding studies involving receptor autoradiography. This technique has been extensively used to map the distributions of the D1 and D2 receptors in brain, specifically allowing the visualization and localization of the protein receptor (12-18).The rat D2 receptor has been cloned (19) and repeats all of the structural features common to the family of guanine nucleotide-binding regulatory protein (G protein)-coupled receptors, including the a2 and 132 adrenergic, muscarinic, rhodopsin, and serotonergic receptors. This family of receptors shares significant sequence similarity in the seven putative transmembrane domains and members ofthe family are highly variable in length and sequence in the region between the fifth and sixth hydrophobic domains, a region that has been associated with G-protein coupling (19,20). With the advent of methods to determine the distributions of specific mRNAs and the cloning of the D2 receptor, it is now possible to visualize mRNAs specific for the D2 receptor protein in the...
Transcript expression for the vesicular glutamate transporter vGlut1 in human hippocampus, visualized by in situ hybridization. For more information on this topic, please see the article by Knable et al on pages 609-620.
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