Glutamatergic/GABAergic system abnormalities in the cerebral cortex and morphological/anatomical/biochemical abnormalities in the thalamus are present in schizophrenia. Some of the evidence comes from studies conducted in our laboratories showing changes in the expression of mRNAs encoding for ionotropic glutamate receptor genes in both the thalamus and the cortex, and for the GABA synthesizing enzyme glutamic acid decarboxylase (GAD-65 and GAD-67). Studies on the same brain specimens derived from extremely well characterized neuropsychiatrically and neuropathologically assessed schizophrenic subjects has shown that GAD mRNA level changes are reflected in functional abnormalities in the activity of GAD. The studies proposed aim to determine whether glutamatergic/GABAergic abnormalities in the neocortex are associated with glutamatergic/GABAergic abnormalities in the thalamus. Brain tissue specimens will be derived from: Dorsolateral prefrontal cortex (DLPFC) and the mediodorsal nucleus (MDN) of the thalamus; Cingulate cortex and the anterior group of thalamic nuclei; Precentral cortex (Brodmann 4/6) and the ventrolateral nuclear group of the thalamus; Inferior temporal gyrus (Brodmann 20) and the pulvinar; and Striate / Visual cortex (Brodmann 17) and the lateral geniculate nucleus of the thalamus. These specimens will be derived from 37 normal controls, 32 antemortem assessed and diagnosed schizophrenics who have been neuropathologically characterized to be free of any confounding neuropathological lesions, and 15 Alzheimer disease cases for comparative purposes. We will test hypotheses designed to determine whether glutamatergic and GABAergic abnormalities (mRNA and protein) in specific thalamic nuclei are associated with glutamatergic and GABAergic abnormalities in specific cortical regions and vice versa. In addition, studies in rats will test the hypothesis that the glutamatergic and GABAergic abnormalities in the prefrontal cortex are a direct result of lesions in the MDN.
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