This proposal describes a series of studies that have emanated from previous investigations in this laboratory suggesting that three replicatible structural differences may exist in schizophrenic cortex. These findings include a) a reduced density of small interneurons, b) an increased number of vertical, associative axons, and c) a decreased size of neuronal aggregates in layer II. the proposed studies will seek to replicate these findings further to evaluate their generalizability and specificity for schizophrenia. In addition, we are proposing to extend these investigations to the entorhinal cortex and hippocampus, two other corticolimbic brain regions implicate in the etiology of this disorder. The first two findings indicated above have lead to the hypothesis that alterations in GABAergic inhibitory and glutamatergic excitatory elements in intrinsic cortical elements may occur in schizophrenic brain. Accordingly, we intend to perform autoradiographic localization of the GABA-A and NMDA-sensitive glutamate receptors to determine whether up- and/or down-regulation, respectively, of these two binding sites may occur in schizophrenics. The benzodiazepine and PCP receptors, which have been implicated in the mediation of symptoms associated with schizophrenia and are also believed to form a complex with the GABA and NMDA binding sites, respectively, will also be studied. The autoradiography will be performed using tritium-labelled ligands and emulsion-dipped coverslips to optimize spatial resolution. This approach will permit quantitative determinations of the numbers of autoradiographic grains found in neuropil versus either small interneurons or large pyramidal cells in individual layers and sub- regions. Dilapidation will be used to control for the effect of differential quenching on the development of grains. The effects of confounding variables such as age, post-mortem interval, fixation, hypoxia and neuroleptic exposure will be evaluated using multivariate statistical approaches. Attempts will be made to determine whether changes in small neurons counts and vertical axon numbers, correlate with alterations in GABA-A or NMDA receptor binding. Overall, the design of these studies is aimed at determining whether the differences occurring among schizophrenic patients may have appeared before, during or after the onset of the illness and be either of etiologic or epiphenomenal significance to this disorder.
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