Hippocampal Retinoid Pathway in Schizophrenia

University Of Pennsylvania, Philadelphia PA

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Abstract

DESCRIPTION: (Applicant's abstract) Evidence suggests that schizophrenia is a developmental disorder involving abnormal connectivity between various cortical and subcortical brain regions including the hippocampus. Retinoid pathway dysregulation has been proposed as an important factor in the etiology of schizophrenia. This pathway plays a central role in development and regulates the expression of many candidate genes for schizophrenia. It also regulates the expression of proteins involved in 1) long-term potentiation (molecular mechanisms of learning and memory) and 2) synaptogenesis. This pathway acts through two families of nuclear receptors highly expressed in the hippocampus, the retinoic (RAR) and retinoid X (RXR) receptors, both existing in three different subtypes (a,beta,y). Understanding how the retinoid pathway is dysregulated in adult schizophrenic brain and how it impacts several proteins associated with plasticity in learning and memory may provide information to how the brain becomes miswired in schizophrenia. In a preliminary study, we found a significant reduction in the proportion of RARa labeled granule cells in the dentate gyrus of schizophrenic subjects, supporting the hypothesis of a dysregulated expression of retinoid receptors in schizophrenia. In aim 1, we will use immunohistochemistry and in situ hybridization to a) test the hypothesis that there is increased RARa protein and mRNA levels in the hippocampus of schizophrenics, b) determine if the increase in RARa mRNA is specific for one of the two RARa isoforms, and c) assess if the expression of other RARs and their respective mRNAs is also affected in schizophrenia. These studies will provide critical information about the possible mechanisms of that dysregulation. In ain 2, we will use the same methods to test the hypothesis that the dysregulated expression of RARs correlate with changes in the expression of two retinoid regulated plasticity proteins: GAP-43 and Fyn and their respective mRNAs. These studies will determine if the transcriptional regulation of Fyn and GAP-43 is affected in schizophrenia. A correlation between RAR expression and Fyn or GAP-43 expression will better define the role of retinoid dysfunction in relation to memory and learning deficits in schizophrenia.