Gene expression studies in schizophrenia have identified a number of transcripts that have altered expression in the cerebral cortex, especially those involved in GABA-ergic and glutamatergic neurotransmission. The goal of this proposal is to place those findings firmly into the context of identified neural circuits in auditory sensory cortex. Single cell gene expression will be evaluated via custom-designed array analysis to compare the expression of multiple transcripts (>570) in distinct neuronal populations believed to be involved in the pathogenesis of schizophrenia. These experiments will identify gene expression pathways as well as specific transcripts that have altered expression, and simultaneously identify the neuron subtypes in which their expression is altered. Stereological measurements of these same neuron populations will determine whether altered gene expression is 1) accompanied by a decrease in the relative density of individual cells types, or 2) reflect gene expression alterations within intact neuronal populations. These two scenarios lead to different conclusions about the cause of altered gene expression in schizophrenia. These data will further our understanding of the etiology of schizophrenia, and provide circuitry-related models to guide pharmacotherapeutic strategies for the treatment of schizophrenia.
Current evidence suggests that specific subsets of inhibitory neurons in the cerebral cortex may be missing, or functionally disrupted in schizophrenia. This proposal will focus on several subtypes of these neurons that are especially suspected to be involved in the pathogenesis of schizophrenia. Their gene expression profile and the relative number will be determined in postmortem samples from schizophrenia and normal brains. The findings will help identify the precise nature of schizophrenia pathology in the cerebral cortex.
