Neuronal basis of sensory processing dysfunction in schizophrenia

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Schizophrenia is a major mental disorder that affects approximately 1% of the population worldwide. Cognitive dysfunction is a core feature of the disorder, reflecting widespread cortical and subcortical neuronal dysfunction. The goal of the overall Center is to investigate mechanisms underlying sensory processing disturbances in schizophrenia, with particular emphasis on glutamatergic/NMDA-related mechanisms. Cortical processing disturbances in schizophrenia in general have been linked to altered expression of calcium binding proteins within GABA-ergic interneurons, possibly reflecting secondary down regulation due to primary failure in glutamatergic drive. This Project will examine cell density and gene expression profiles of GABA-ergic interneurons in primary visual cortex in schizophrenia, using laser capture microdissection coupled with gene array expression techniques developed at NKI/NYUSoM by the Project Leader, Dr. Ginsberg, and will build as well from a prior gene array study of hippocampal stellate cells in schizophrenia showing reduced NMDA receptor-related expression. The project co-leader. Dr. Smiley, is an expert histologist who is pursuing ongoing studies of calcium binding protein/GABA interneuron density in auditory cortex as part of an NlMH-funded project. Decreased parvalbumin expression has been extensively documented in prefrontal cortex in schizophrenia, but sensory regions have been studied to only a limited degree. For the NKI component of the study, quantitative morphometric analyses will be performed on postmortem visual cortex from schizophrenia and control subjects. Immunocytochemistry will be used to identify GABA interneuron cell types, including pavalbumin, calbindin and calretinin cell types. Relative density of GABA interneurons will then be compared between schizophrenia and control groups. Finally, using laser capture microdissection, select populations of calbindin and parvalbumin neurons will be obtained and processed for gene array analysis by Dr. Ginsberg. Gene array analysis will analyze expression level of calcium binding proteins, glutamate-related constructs and other more general gene families.