The etiological complexity of schizophrenia has prompted its parsing into endophenotypes, to facilitate genetic and biochemical study. The Center investigators found that the alpha7 nicotinic receptor subunit gene (CHRNA 7) is genetically linked to both a deficit in inhibitory gating of auditory response and to schizophrenia. Polymorphisms in the core CHRNA 7 promoter that decrease the gene's expression are associated with both schizophrenia and with diminished auditory gating. In the proposed Center, we will continue to identify CHRNA7 polymorphisms (Project 1). Second, we will determine if the polymorphisms reduce receptor expression and related cellular functions such as calcium flux in human olfactory neurons (Projects 1 and 2). Third, we will determine the effects of these polymorphisms on brain functions, including P50 sensory gating. (Project 0003). We will also consider effects of the polymorphisms on development of inhibitory neuronal circuitry in humans and animal models from the perinatal period through adulthood (Projects 4 and 5). Fourth, we will determine to what extent agonists directed against the alpha7 receptor reverse this pathophysiology and the symptoms of schizophrenia (Project 5). We provide new data to show: (1) diminished binding of transcription factors to the CHRNA7 promoter in schizophrenia, (2) decrease by nicotine of the hippocampal hemodynamic hyperactivity that we previously reported in fMRI studies of schizophrenics, and (3) deficits in learning in mice with the acra7 (murine CHRNA 7) null mutation, as well as evidence in humans that P50 abnormalities correlate with decreased declarative memory. We present provocative new data that perinatal choline supplementation to mice with acra7 polymorphisms results in offspring with normal inhibition of the hippocampal response to repeated sounds.
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