Both the rostral entorhinal (ERC) and dorsolateral prefrontal (PFC) cortices have been implicated as sites of dysfunction in schizophrenia. In addition findings from both preclinical and clinical investigations have suggested that abnormalities in dopamine (DA) afferents and/or GABA local circuit neurons could be critical contributors to the dysfunction of these regions in this disorder. However, information from postmortem studies on the integrity. of cortical DA and GABA systems in schizophrenia is limited, and the possible interrelationships between alterations in these systems have not been examined. Furthermore, understanding the possible functional significance of alterations in these neurotransmitter systems in schizophrenia requires that they be considered within the context of the cortical circuits that they influence. During the current period of funding, we have used the macaque monkey as a guide to the organization of the human cortex in order to develop models of the neural circuitry of the PFC and ERC that incorporate DA afferents and the different subpopulations of GABA local circuit neurons. Guided by this circuitry, the proposed studies will test seven specific hypotheses that address the following general questions regarding the integrity of, and the relationships between, DA and GABA systems in the ERC and PFC of schizophrenic subjects: 1) Is the DA innervation of ERC and PFC selectively altered in schizophrenia? 2) Are there abnormalities in specific subpopulations of GABA local circuit neurons in these same regions? 3) Do these alterations in DA and certain classes of GABA cells reflect a selective DA synaptic input to those classes of local circuit neurons? The power of the proposed research strategy results from the integration of studies of both DA and GABA systems in postmortem brain specimens from the same cohort of carefully-characterized schizophrenic subjects, and the use of nonhuman primate investigations to both guide and interpret the results of the human studies.
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