CORE--MOLECULAR AND CELLULAR

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The goal of the Molecular and Cellular Core is to provide the resources and technologies to study gene expression and to assess putative neuropathological changes in the animal models being developed in the Center (Projects by Javitt, Kandel, and Rayport). The rationale for performing gene expression profiling on animal models is based on the fact that the developmental and genetic manipulations will all induce long lasting changes in gene expression and that these changes are likely to contribute to the phenotype of the animal models. In keeping with the hypothesis that cortical glutamatergic dysfunction will result in an imbalance in subcortical dopamme function (cortical DA deficit and striatal DA hyperactivity), we expect that changes in gone expression will take place both in the prefrontal cortex and in the striatum (See general description of the Center). The mouse and monkey expression profiles will be compared not only with one another but also with data from schizophrenic patients (collaboration with Karoly Mimics, University of Pittsburgh). These multiple comparisons should enable us to establish correlations between specific gene expression profiles and the physiological and behavioral phenotypes of the animal models. This Core will also perform histopathological analyses of the tissue from the animal models. The neuropathological analysis will serve multiple purposes, notably 1) to provide histological stereological protocols necessary to localize changes in gene expression and protein levels and quantify them at the cellular level and 2) to provide qualitative and quantitative histopathological ?survey? of the brain (cell density, cell morphological profiles, regional volume) to assess if the models replicate the morphometric and histopathological abnormalities observed in schizophrenia. A ?schizophrenia signature? may be a gene expression profile that is common to several manipulations that induce the same constellation of physiological, behavioral, neurochemical, and histopathological phenotypes. The candidate genes, which will emerge from these studies, will inform the human components of this Center (Projects by Abi-Dargham and Laruelle), clinical Core) by pointing toward specific molecular pathways within specific neuronal populations that may be altered in schizophrenia. Such knowledge may ultimately lead to the development of new therapies aimed at correcting these alterations.