Biochemical Mechanisms Mediating Cell Type-Specific Actions of Antipsychotic Drug

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Project 3 will address the major theme of the Conte center "Identification of cell type-specific actions of antipsychotic drugs" by taking primarily biochemical approaches to characterize key signaling proteins believed to be involved in the effects of antipsychotic drugs on specific aspects of neuronal function within corticostriatal circuits. In Aim 1, Project 3 will follow up from recent studies carried out in collaboration with Project 1 that have found that the protein DARPP-32, which is highly enriched in all striatal medium spiny neurons (MSNs), regulates chromatin function through a novel mechanism involving phosphorylation/dephosphorylation and nuclear translocation. Other studies indicate that DARPP-32 is required for the effects of haloperidol on regulation of MSN gene expression. Project 3 will elucidate the role of DARPP-32's nuclear function in the actions of antipsychotic drugs. These studies will be carried out in collaboration with Dr. Nestler, and will be integrated with Project 4's studies of chromatin remodeling. In Aim 2, building on results obtained in collaboration with Dr. Surmeier (Project 5) that show specific effects of the typical antipsychotic haloperidol on the dendritic morphology of striatonigral and striatopallidal (MSNs), Project 3 will identify the biochemical basis for the observed effects of haloperidol. In collaboration with Projects 2 and 5, these studies will be expanded to analysis of the biochemical effects of atypical antipsychotic drugs on the structure of MSNs, as well as of both typical and atypical classes of drug on corticostriatal projection neurons. In these studies, Project 3 will make use of translational profiling data from Projects 1 and 2, as well as gene expression data from Project 4, to identify candidate genes involved in control of MSN structure. In Aim 3, Project 3 will work together with Project 2 in the development of new methods to exploit the power of transgenic mouse models to allow for systematic biochemical and proteomic analysis of specific neuronal cell populations within corticostriatal circuits. Project 3 will also contribute biochemical expertise to ongoing studies by the other projects, as well as contribute to future studies that are carried out collectively by the Conte Center as a result of new discoveries made.