(provided by PI): Schizophrenia is a chronic and debilitating mental illness with a prevalence of approximately 1%. A number of candidate genes are presently being investigated, although none has been definitively connected to the etiology of the disorder. Genetic linkage and biochemical studies support the investigation of the a7 nicotinic acetylcholine receptor gene (CHRNA7) as one of these candidate genes. The a7 gene has been designated by the MATRICS study group as an important receptor for development of drugs for cognition in schizophrenia. The a7* receptor is the target of nicotine in tobacco, a product used excessively in the schizophrenic population. Although smoking has declined in this country over the last twenty years, it has not decreased in in schizophrenics where >80% are heavy smokers. The a7 nicotinic receptor (a7*) has been implicated in cognitive and sensory deficits in schizophrenia, making regulation of this gene an important research problem for drug development. Surface expression of the a7* receptor, is decreased in postmortem brain of schizophrenic patients. Recent data from our laboratory shows that mRNA and protein levels for CHRNA7 are low in schizophrenic non-smokers, but brought to control levels or normalized in schizophrenic smokers, suggesting a defect in either transcription or translation. As the surface binding for this receptor is low in schizophrenic postmortem brain, the findings also suggest that assembly and trafficking of the receptor may be aberrant. This proposal will investigate three possible mechanisms for regulation of expression of the CHRNA7 gene in control and schizophrenic smokers and non-smokers (4 groups): 1) comparison of transcription of the gene. 2) comparison of translation, and 3) comparison of receptor assembly. Our hypothesis is that at one or more of these steps, there is a deficit in gene regulation of the CHRNA7 gene in schizophrenic subjects. The completion of this work will determine whether the hypothesized mechanisms are operative, contributing to the low levels of surface binding seen in postmortem brain of schizophrenic subjects. Lay statement: Schizophrenia is a chronic and debilitating illness with a strong genetic component. Several candidate genes are being studied, including the a7 nicotinic acetylcholine receptor, which responds to smoking. The prevalence of smoking in schizophrenia is very high, suggesting a form of self-medication. This proposal will investigate the regulation of the a7 nicotinic receptor gene in postmortem brain of control and schizophrenic smokers and non-smokers. ? ?
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