This application seeks to identify and characterize the nature and localization of anatomic and chemical abnormalities in the limbic cortex of schizophrenic (hippocampus, entorhinal cortex, and anterior cingulate) contributing to the pathophysiology of the disease. Several laboratories have generated data suggesting limbic pathology in schizophrenia; our own in vivo imaging and postmortem studies (see Prelim Data) suggest a limbic focus as well. Recently, data from Csernansky et al, have suggested that pathology in the hippocampus is not homogeneous, but is localized within that structure to the lateral head of the hippocampus and the medial aspect of the body (subiculum); this might explain the variability of outcomes reported across studies in postmortem analyses, because few studies control for hippocampal axis. To answer this question, we have paired anatomic and neurochemical measures within the hippocampus, entorhinal cortex, and anterior cingulate from anterior to posterior extent, quantifying markers of neuronal structure and transmission, which may be abnormal in schizophrenic limbic cortex. The hypothesis driving this work is based on our in vivo imaging data from patient studies and our animal model work, which are extensively in agreement with the published literature. We have raised the speculative hypothesis that positive symptoms in schizophrenia are associated with reduced glutamatergic activity at the NMDA receptor in the hippocampus. The resulting reduction in the activity of the glutamatergic hippocampal efferent signal to its projection fields, including entorhinal cortex, anterior thalamus, and anterior cingulate may underlie the generation of psychotic symptoms in schizophrenia. 24 postmortem schizophrenia brains with paired EC, hippocampi and cingulates will be compared to the same structures in 24 matched healthy and 12 matched psychotic control brains. We will study neuronal number, synaptic and dendritic density, along with neurochemical measures of the glutamate, and GABA, systems along the A-P- extent of these structures. We postulate that only certain regions of hippocampus will be affected (lateral head and medial body), and that the neurochemical abnormalities in these regions will colocalize with neuronal number and/or synaptic and dendritic changes, and that related regions of hippo, EC, and ACC will be affected. These data will have implications for understanding the mechanisms of the illness and for directing future new drug discovery for schizophrenia therapeutics.
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