Project 3 identified CHRNA7 as the gene that is linked to the PSO sensory gating abnormality in schizophrenia and found functional SNPs in the core promoter of the gene that are associated with this abnormality. Genetic linkage to 15q13.3, the locus of CHRNA7 has been found in multiple ethnic groups, and recent evidence suggests that rare deletions of the gene are associated with schizophrenia. The human molecular biology studies in this Project characterize mutation, function, and regulation of CHRNA7. To fulfill the need for clinically useful genomics, the human molecular biology project has undertaken extensive screening of CHRNA7 to find its pathogenic mutations. A critical finding is that the amino acid structure of the protein is generally normal in schizophrenia and thus most abnormalities involve regulation of its expression. Project 1 has used that information to design a new therapeutic. Project 3 will continue to support drug development by identifying new polymorphisms, one of which already shows preliminary evidence of a pharmacogenetic effect. Investigation of the 5'and 3'regulatory regions in Aim 1 interacts with similar efforts of Project 4 in DBA/2 mice, which also have CHRNA7 mutations. Functional mutations in human CHRNA7 N' be introduced into transgenic mouse models in Project 5. Genotypes may eventually identify individuals who are likely to have genetically determined pathobiology involving a7nAChRs. Project 2's preventive intervention in infancy similarly requires information about CHRNA7 and other genes that convey risk for schizophrenia such as NRG1, a gene associated with risk for schizophrenia that is involved in the developmental expression of aTnAChRs.
Aim 2 will determine how NRG1 and CHRNA7 polymorphisms both act to increase risk for schizophrenia. Psychiatric molecular biology in the Center includes more than genomics. Project 2 is now involved in perinatal treatment with choline as an a7nAchR agonist.
In Aim 3, Project 3 will contribute its microarray technology to characterize the changes in gene expression that result in animal models from Projects 4-6 that receive this treatment. Results will be compared with our previous experience in characterizing gene expression in postmortem brain from persons who had schizophrenia. Project 3 provides basic research support to Projects 1 and 2 and interacts with basic researchers in Proiects 4, 5, and 6. It receives statistical qenetics support from Core B.
New therapeutic strategies for schizophrenia are needed to improve cognitive dysfunction and negative symptoms and to prevent the development of psychosis. The Center investigates a nicotinic acetylcholine receptor as a new therapeutic target. Investigational results are used to design a new drug treatment for schizophrenia and a preventative nutrient intervention during infant development, both of which activate this ri^r.e^riirsr
|Wilking, Jennifer A; Stitzel, Jerry A (2015) Natural genetic variability of the neuronal nicotinic acetylcholine receptor subunit genes in mice: Consequences and confounds. Neuropharmacology 96:205-12|
|Bates, R C; Stith, B J; Stevens, K E et al. (2014) Reduced CHRNA7 expression in C3H mice is associated with increases in hippocampal parvalbumin and glutamate decarboxylase-67 (GAD67) as well as altered levels of GABA(A) receptor subunits. Neuroscience 273:52-64|
|Stevens, Karen E; Choo, Kevin S; Stitzel, Jerry A et al. (2014) Long-term improvements in sensory inhibition with gestational choline supplementation linked to ?7 nicotinic receptors through studies in Chrna7 null mutation mice. Brain Res 1552:26-33|
|McClure-Begley, Tristan D; Grady, Sharon R; Marks, Michael J et al. (2014) Presynaptic GABAB autoreceptor regulation of nicotinic acetylcholine receptor mediated [(3)H]-GABA release from mouse synaptosomes. Biochem Pharmacol 91:87-96|
|Wildeboer-Andrud, Kristin M; Zheng, Lijun; Choo, Kevin S et al. (2014) Cotinine impacts sensory processing in DBA/2 mice through changes in the conditioning amplitude. Pharmacol Biochem Behav 117:144-50|
|Law, Amanda J (2014) Genetic mouse models of neuregulin 1: gene dosage effects, isoform-specific functions, and relevance to schizophrenia. Biol Psychiatry 76:89-90|
|Tregellas, Jason R (2014) Neuroimaging biomarkers for early drug development in schizophrenia. Biol Psychiatry 76:111-9|
|Tregellas, Jason R; Smucny, Jason; Harris, Josette G et al. (2014) Intrinsic hippocampal activity as a biomarker for cognition and symptoms in schizophrenia. Am J Psychiatry 171:549-56|
|Paterson, Clare; Wang, Yanhong; Kleinman, Joel E et al. (2014) Effects of schizophrenia risk variation in the NRG1 gene on NRG1-IV splicing during fetal and early postnatal human neocortical development. Am J Psychiatry 171:979-89|
|Smucny, Jason; Stevens, Karen E; Tregellas, Jason R (2014) Acute administration of ?? tetrahydrocannabinol does not prevent enhancement of sensory gating by clozapine in DBA/2 mice. Pharmacol Biochem Behav 118:22-9|
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