CORTICAL/SUBCORTICAL CIRCUITS IN SCHIZOPRHENIC BRAIN

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This is a proposal to study cortical-subcortical neurochemical circuitry in postmortem brain in schizophrenia. Dysregulation of dopaminergic neurotransmission has been frequently implicated in the pathogenesis and/or symptomatology of schizophrenia, since all antipsychotic medications affect the dopamine system in some fashion. The original "dopamine hypothesis of schizophrenia" posited an increase in dopaminergic activity in the brain in this illness, but more recent evidence has led to a reconceptualization of this view. Specifically, the current view is that there is diminished dopaminergic activity in the cortex, which in turn leads to increased dopaminergic activity in the striatum. This interaction has been postulated to be transmitted via glutamatergic corticostriatal projections. Subsequent refinement suggests that corticostriatal glutamatergic and mesostriatal dopaminergic efferents converge in the striatum, and the dynamic balance between these two systems may be of importance in schizophrenia. Specifically, it has been suggested that schizophrenia may be associated with diminished glutamatergic or increased dopaminergic tone in the striatum, as part of a larger limbic circuit. Surprisingly, relatively little work has been done to date to examine these modified versions of the original dopamine hypothesis of schizophrenia. In our proposed work, we will employ the examination of messenger RNAs encoding dopamine and glutamate receptors in sectioned postmortem brain tissue to address the anatomically specific expression of these receptor genes, using a well-characterized set of tissue. These studies will allow the examination of these recent hypotheses of the involvement of the dopaminergic and glutamatergic regulation of cortical- subcortical circuits in schizophrenia, namely that (1): the brain dopamine systems are differentially regulated in schizophrenia, manifesting increased tone in the striatum but diminished activity in the limbic cortex; and (2) schizophrenia is associated with dysregulation of a feedback circuit consisting of corticostriatal glutamatergic and mesostriatal dopaminergic systems that mutually determine the activity of a striatothalamocortical information-processing network. This work represents the beginning of a comprehensive examination in human brain of these hypotheses of the neurochemistry and neuroanatomy underlying schizophrenia. These studies will provide a greater understanding of the circuitry underlying this illness, and how and where it may be disrupted.