Regarding normal human brain development, our group examined pre- and post-synaptic markers of the dopamine (DA) system in postmortem tissue across the lifespan (2 months to 86 years). We measured levels of tyrosine hydroxylase (TH), the rate limiting enzyme in DA biosynthesis and measured the three most abundant DA receptors (DARs) in the human prefrontal cortex (PFC). We found that the DARs mRNA levels varied with age. The peak increase in DAR1 mRNA levels around adolescence to early adulthood may be of particular importance to neuropsychiatric disorders, such as schizophrenia (SCZ), in which symptoms manifest during this developmental period. Another study measured levels of mRNA of glucocorticoid and their receptors (GRs) in the PFC and hippocampus across 5 age groups, from infants to aged. GRs are implicated in dynamic cognitive and neuroendocrine processes mediated by the PFC and hippocampus. GRs may differentially influence behavior and disease susceptibility. We did not detect a main effect of age in the hippocampus but we did see an effect in the PFC with the greatest expression in adolescence and adults. This suggests that human GR regulation of cognition and neuroendocrine stress response may be more apparent during late maturation and at maturity. And finally, we examined catechol-o-methyltransferase (COMT) enzyme activity and protein expression in PFC in 6 age groups of normal controls from neonates to the aged. We found a significant increase in COMT enzyme activity from neonate to adulthood and this is paralleled by increases in protein expression. Additionally, COMT protein expression is related to the Val158Met genotype. These increases may reflect changes in the PFC DA system and stresses the increasing importance of COMT for PFC dopamine regulation during maturation. ? ? The recent identification of the NRG1 receptor, ErbB4 as a candidate risk gene for SCZ, has prompted the notion that other molecules in the NRG1 pathway maybe involved in the disorder. ErbB4 is a type 1 receptor tyrosine kinase that regulates cell growth, proliferation and differentiation. It has been shown that a molecular mechanism contributing to the genetic association of the NRG1 gene with SCZ involves altered transcriptional regulation of a novel variant of the gene. We examined ErbB4 splice variant gene expression in the hippocampus and DLPFC. ErbB4 splice patterns remain unaltered in the hippocampus in SCZ, however we observed a large increase in expression of only the splice variant containing exon 16 (JM-a) and exon 26 (CYT-1) variant isoform mRNAs in DLPFC in SCZ, suggesting that an ErbB4 receptor that contains both JM-a and CYT-1 domains is preferentially upregulated in the disease. ? ? Cortical dysfunction has been implicated in the pathophysiology of SCZ. Decreased expression of the gamma-aminobutyric acid (GABA) synthetic enzyme glutamic acid decarboxylase 67 (GAD67), encoded by GAD1, is found in SCZ postmortem brain. We report evidence of distorted transmission of single nucleotide polymorphism (SNP) alleles in 2 independent SCZ family-based samples. In both samples, allelic association was dependent on the gender of the affected offspring and one sample was COMT Val158Met genotype dependent. Analysis revealed that variation in GAD1 influenced cognition, attention and working memory (WM). A SNP affecting cognition was associated in unrelated healthy controls with inefficient activation of PFC during WM task. Another SNP that influenced cognition was associated with decreased expression of GAD1 mRNA in the PFC of SCZ brain. Finally, we observed evidence of statistical epistasis, when one gene causes another gene to be either unexpressed or its affect masked, between SNPs in COMT and GAD1. This suggests that the mechanism involves altered cortical GABA inhibitory activity, perhaps modulated by DA function. This study is the result of an in silico prediction and validity is yet to be determined experimentally. Increased risk for complex illness genetically is depended upon many genes with subtle effects. All samples tested produced positive clinical associations, our risk SNPs and alleles are so similar, genetic variation impacts on cortical function. This suggests that GAD1 may be a risk factor for SCZ. And finally, the observation that an interaction with COMT adds biologic plausibility for genes increasing risk for illness shows the importance of epistatic effects in mediating the strength of genetic association in psychiatric disorders.? ? DA- and cAMP-regulated phosphoprotein (DARPP-32) encoded by PPP1R1B is a pivotal integrator of information in dopaminergic neurons, regulating the response to neuroleptics, psychotogenics, and drugs of abuse, affecting striatal function and plasticity. In this study, we identify a common PPP1R1B haplotype which predicts mRNA expression of PPP1R1B isoforms in postmortem human brain. This haplotype is associated with enhanced performance on cognitive tests. Multimodal imaging of healthy subjects revealed an impact of the haplotype on neostriatal volume, activation, and functional connectivity of the PFC. The haplotype was associated with risk for SCZ in 1 family-based analysis. Our results identify a prefrontal-neostriatal system affected by variation in PPP1R1B and suggest DARPP-32 plays a pivotal role in cognitive function and possibly the pathogenesis of SCZ.? ? Previous studies have implicated regulator of G-protein signaling 4 (RGS4) as a candidate SCZ susceptibility gene. In the CBDB/NIMH and Stanley Array Collection, we compared RGS4 mRNA expression in the DLPFC of normal controls and patients with SCZ and in the hippocampus in the CBDB/NIMH collection. We examined the effects of 4 previously identified risk SNPs on RGS4 expression levels in these cohorts. There was no difference in RGS4 expression levels between SCZ patients and controls and no association between the RGS4 risk SNPs and RGS4 expression. However, COMT Val158Met genotype was associated with PFC and hippocampal RGS4 mRNA expression, with COMT Val showing lower expression then Val/Met or Met/Met. Consistent with these findings, RGS4 mRNA was inversely correlated with COMT enzyme activity in DLPFC. These data suggest that RGS4 mRNA expression is associated with cortical DA signaling and demonstrates the importance of genetic and/or environmental background in gene expression studies in SCZ.? ? Microarray analysis identified KIAA0513 as upregulated in the DLPFC of subjects with SCZ as compared with controls. KIAA0513 interacts with genes that interact with proteins involved in neuroplasticity, apoptosis, and cytoskeletal regulation. KIAA is likely to be involved in signaling pathways related to these processes. We characterized KIAA, confirmed the differential expression in subjects with SCZ and identified putative interacting proteins. KIAA was highly expressed in the SCZ DLPFC. Although we cannot conclusively determine the function of KIAA, the present study suggests that the protein may be involved in neuroplasticity, cytoskeletal regulation, and apoptosis. ? ? PFC is involved in the neurobiological circuitry that promotes drug use and drug-seeking behavior and for various drugs of abuse. We speculate that multiple types of drug abuse would share common transcriptional changes, due to similar changes in cellular function. Clustering of transcriptional profiles and examination of changes in individual transcripts showed consistent changes in gene expression in a majority of cases. Functionally, this may relate to the decreased frontal white matter volume observed in drug abusers. Neurons have a unique organization of their secretory pathway. In that context, the shared increases in transcription of genes relating to transport functions suggests that changes in PFC dendritic function and plasticity is shared among drug abuse cases.
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