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Little is known about chromosomal loopings involving proximal promoter and distal enhancer elements regulating GABAergic gene expression, including changes in schizophrenia and other psychiatric conditions linked to altered inhibition. Here, we map in human chromosome 2q31 the 3D configuration of200 kb of linear sequence encompassing the GAD I GABA synthesis enzyme gene locus, and we describe a loop formation involving the GAD1 transcription start site and intergenic noncoding DNA elements facilitating reporter gene expression. The GADl-TSS-50kbLoop was enriched with nucleosomes epigenetically decorated with the transcriptional mark, histone H3 trimethylated at lysine 4, and was weak or absent in skin fibroblasts and pluripotent stem cells compared with neuronal cultures differentiated from them. In the prefrontal cortex of subjects with schizophrenia, GADl-TSS-50kbLoop was decreased compared with controls, in conjunction with downregulated GAD1 expression. We generated transgenic mice expressing Gad2 promoter-driven green fluorescent protein-conjugated histone H2B and confirmed that Gadl-TSS-55kbLoop, the murine homolog to GADl-TSS-50kbLoop, is a chromosomal conformation specific for GABAergic neurons. In primary neuronal culture, Gadl-TSS-55kbLoop and Gadl expression became upregulated when neuronal activity was increased. We conclude that 3D genome architectures, including chromosomal loopings for promoter-enhancer interactions involved in the regulation of GABAergic gene expression, are conserved between the rodent and primate brain, and subject to developmental and activity-dependent regulation, and disordered in some cases with schizophrenia. More broadly, the findings presented here draw a connection between noncoding DNA, spatial genome architecture, and neuronal plasticity in development and disease. [ABSTRACT FROM AUTHOR]

Suicidal behaviors are frequent in mood disorders patients but only a subset of them ever complete suicide. Understanding predisposing factors for suicidal behaviors in high risk populations is of major importance for the prevention and treatment of suicidal behaviors. The objective of this project was to investigate gene expression changes associated with suicide in brains of mood disorder patients by microarrays (Affymetrix HG-U133 Plus2.0) in the dorsolateral prefrontal cortex (DLPFC: 6 Non-suicides, 15 suicides), the anterior cingulate cortex (ACC: 6NS, 9S) and the nucleus accumbens (NAcc: 8NS, 13S). ANCOVA was used to control for age, gender, pH and RNA degradation, with P≤0.01 and fold change±1.25 as criteria for significance. Pathway analysis revealed serotonergic signaling alterations in the DLPFC and glucocorticoid signaling alterations in the ACC and NAcc. The gene with the lowest p-value in the DLPFC was the 5-HT2A gene, previously associated both with suicide and mood disorders. In the ACC 6 metallothionein genes were down-regulated in suicide (MT1E, MT1F, MT1G, MT1H, MT1X, MT2A) and three were down-regulated in the NAcc (MT1F, MT1G, MT1H). Differential expression of selected genes was confirmed by qPCR, we confirmed the 5-HT2A alterations and the global down-regulation of members of the metallothionein subfamilies MT 1 and 2 in suicide completers. MTs 1 and 2 are neuro-protective following stress and glucocorticoid stimulations, suggesting that in suicide victims neuroprotective response to stress and cortisol may be diminished. Our results thus suggest that suicide-specific expression changes in mood disorders involve both glucocorticoids regulated metallothioneins and serotonergic signaling in different regions of the brain. [ABSTRACT FROM AUTHOR]

Gene expression changes in neuropsychiatric and neurodegenerative disorders, and gene responses to therapeutic drugs, provide new ways to identify central nervous system (CNS) targets for drug discovery. This review summarizes gene and pathway targets replicated in expression profiling of human postmortem brain, animal models, and cell culture studies. Analysis of isolated human neurons implicates targets for Alzheimer's disease and the cognitive decline associated with normal aging and mild cognitive impairment. In addition to τ, amyloid-β precursor protein, and amyloid-β peptides (Aβ), these targets include all three high-affinity neurotrophin receptors and the fibroblast growth factor (FGF) system, synapse markers, glutamate receptors (GluRs) and transporters, and dopamine (DA) receptors, particularly the D2 subtype. Gene-based candidates for Parkinson's disease (PD) include the ubiquitin–proteosome system, scavengers of reactive oxygen species, brain-derived neurotrophic factor (BDNF), its receptor, TrkB, and downstream target early growth response 1, Nurr-1, and signaling through protein kinase C and RAS pathways. Increasing variability and decreases in brain mRNA production from middle age to old age suggest that cognitive impairments during normal aging may be addressed by drugs that restore antioxidant, DNA repair, and synaptic functions including those of DA to levels of younger adults. Studies in schizophrenia identify robust decreases in genes for GABA function, including glutamic acid decarboxylase, HINT1, glutamate transport and GluRs, BDNF and TrkB, numerous 14-3-3 protein family members, and decreases in genes for CNS synaptic and metabolic functions, particularly glycolysis and ATP generation. Many of these metabolic genes are increased by insulin and muscarinic agonism, both of which are therapeutic in psychosis. Differential genomic signals are relatively sparse in bipolar disorder, but include deficiencies in the expression of 14-3-3 protein members, implicating these chaperone proteins and the neurotransmitter pathways they support as possible drug targets. Brains from persons with major depressive disorder reveal decreased expression for genes in glutamate transport and metabolism, neurotrophic signaling (eg, FGF, BDNF and VGF), and MAP kinase pathways. Increases in these pathways in the brains of animals exposed to electroconvulsive shock and antidepressant treatments identify neurotrophic and angiogenic growth factors and second messenger stimulation as therapeutic approaches for the treatment of depression.Neuropsychopharmacology (2009) 34, 18–54; doi:10.1038/npp.2008.172; published online 15 October 2008 [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Deals with a study which examined changes in gene expression during the process of neuroblastoma differentiation using human gene microarray. Methods; Results; Conclusions.

Editorial. Discusses the contributions of microarray technology to neuroscience. Description of the technology; Implications on other forms of biological research; Type of probe in microarray platforms used to examine gene expression.

Presents information on a study which described the bioinformatic selection of human complementary DNA arrayed on nylon membranes at high density for neuroscience applications. Methods; Results; Discussion.