The studies described in this section aim to elucidate the potential mechanisms that may be related to changes in GABAergic and glutamatergic function in the HIPP of schizophrenic (SZ) brain. Recent experiments in rodents have indicated that changes in the GABA system similar to those seen in the HIPP of SZs can be induced by acute infusion of the Gln with the GABAA antagonist, PICRO, which presumably results in an increase in the activation of afferents to the HIPP. We will determine whether chronic activation of the HIPP via the AMYG can produce changes similar to those seen in the postmortem schizophrenic brain: a) a sustained decrease of GABAergic terminals, b) an uncoupled increase of GABAA receptors, c) a decrease of the GluR5,6,7 subunit on apical dendrites and d) a decrease of non-pyramidal neurons (non-PNs). In addition the experiments describe din this section will consider how physiologically induced alterations of GABAergic function in the HIPP formation may influence HIPP cellular firing patterns and associated memory performance. Rats with multiple tetrodes chronically implanted in sectors CA3 or CA1 will be used to assess the nature and plasticity of spatial memory representations in rats with and without AMYG-HIPP activation. In addition, we will explore the spatial learning and memory capacity of similar prepared animals, and relate memory performance with spatial representations that predict memory driven responses. We will test the hypothesis that synaptic and cellular abnormalities we will correlate with the degree of impairment in spatial representation and spatial memory performance, and that these effectors will occur in proportion to the length and/or intensity of exposure to AMYG activation. This model has broad relevance to the cognitive and fMRI studies on schizophrenic Projects V and VI and interdigitate with the hippocampal neurophysiologic studies in Projects II and III.
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