The hypothesis for the Center is based on the findings that the full range of symptoms of schizophrenia are induced by antagonists of the NMDA receptor, that selective loss of GABAergic interneurons occurs in the cortico-limbic system in the disorder that there are glutamatergic synapses on the cortico-limbic pyramidal cells and interneurons where NMDA mediated synaptic neurotransmission is of particular importance. Thus we hypothesize that NMDA receptor mediated neurotransmission is disrupted in schizophrenia and that the resulting changes in information processing by interneuron/pyramidal cell circuitry leads to the cognitive, sensory and motivational abnormalities characteristic of the disease. The proposed studies are directed at testing this hypothesis at multiple and inter-related levels of analysis. Project I will disrupt hippocampal GABAergic neurons by infusions of picrotoxin in the amygdala and the effects of hippocampal physiology and on memory will be determined. Project II will compare the effects of dopamine and of NAAG on post- synaptic responses of the two glutamatergic inputs to the hippocampal CA1 region, the perforant pathway and the Schaffer collaterals by monitoring currently and Ca2+ influx into spines in rat hippocampal slices. Project III will focus on the differences in the NMDA receptor characteristics of the interneurons versus the pyramidal cells in CA1 as monitored by whole cell clamp in the rat hippocampal slice following Schaffer collateral stimulation. The effects of aminophosphonovalerate (AVP), receptor isolated conditions. Project IV will further characterize human GCPII in schizophrenia by identifying allelic variants and carrying out extensive post-mortem studies on glutamatergic markers in schizophrenic brains and in vivo analysis of peripheral markers of glutamatergic neurotransmission and GCPII activity. Project V will use magnetic resonance imaging to correlate alterations in N-acetyl aspartate and NAAG with symptom characterizations and response to D- cycloserine in the clinical studies of Project VI. Project VI in collaboration with Project IV will look for correlates between symptomatic features and peripheral markers of glutamatergic neurotransmission and of GCPII activity. Project V will use magnetic resonance imaging to correlate alterations in N-acetyl aspartate and NAAG with symptom characterizations in response to D-cycloserine in the clinical studies of Project VI. Project VI in collaboration with Project IV will look for correlates between symptomatic features and peripheral markers of glutamatergic neurotransmission and of GCPII activity. Placebo controlled trials of the NMDA receptors glycine modulatory site partial agonist, D-cycloserine, and of the full agonist, D. serine, will be carried out to compare their effects and identify predictors of clinical response. A Computational Core will play a major role in integrating findings across Projects on the NMDA receptor hypofunction hypothesis of schizophrenia and in developing predictive models.
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