The overall aim of this Project is to focus on two molecular targets, synapsin I and the alpha7 neuronal nicotinic acetylcholine receptor as candidate genes, identified in Projects 1 and 3, that mediate neuronal dysfunction in schizophrenia. Both positive and negative results will be returned to the other investigators where they will contribute to the design of future experiments and toward a model for isolation of the genetic determinants of this disease. While clinical and animal model studies can suggest a neuronal mechanism for dysfunction and implicate specific neurotransmitters or receptors, it remains to demonstrate that an actual deficit in structure or function in a specific molecular target correlates with schizophrenia. The neuronal nicotinic acetylcholine receptor system has been linked to abnormalities in auditory evoked responses in schizophrenics and first-degree relatives by Project 1. Further, decreased levels of a specific nicotinic receptor, alpha7, have been associated with an auditory gating deficit in both rats and mice by Project 3. Our preliminary data suggest that there may be a decreased population of this receptor in schizophrenics, as well. This Project will measure receptor levels, mRNA levels and examine the coding sequence of the alpha7 gene for polymorphisms in postmortem brain isolated from a large number of schizophrenics and controls. We have also found significant deficits, associated with schizophrenia, in the expression of the synapsins, synaptic proteins which regulate the release of neurotransmitters. Such a deficiency could have profound effects on synaptic transmission. This work will be confirmed and the regional deficiency determined. We will work closely with the clinical, animal model and linkage projects, where other candidate genes may be suggested and where the heritability of any genetic defects we identify can be tested. We will also provide molecular biology support for other projects such as functional analysis of the GABAa-beta1 mutation associated with schizophrenia by linkage in Project 2 and analysis of the effects of trophic factors on xenotransplants in Project 7.
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