In the present CCNMD we propose to conduct a new program of translational research concerned with the endogenous processes responsible for cognitive dysfunctions of the dorsolateral prefrontal cortex (DLPFC) in schizophrenia and related disorders. The central hypothesis of the proposal is based on a new set of findings pointing to deficiencies in Ca2-associated intracellular cascades in schizophrenia, among them the recent discovery of a new class of dopamine (DA) receptor interacting proteins (DRIPs) which affect calcium signaling in model systems. We propose that such deficiencies, which may arise from many causes, constitute the underlying causal mechanism in the disorder and can account for both diverse and widespread neuropathologies as well as prominent vulnerability of higher-order functions. Extensive research inspired by the DA hypothesis of schizophrenia has yet to isolate a clear disease-associated abnormality in any particular component of the DA system, but the role of dopamine in the core cognitive dysfunctions of mental diseases cannot be denied. The present CCNMD is comprised of projects at 4 different universities designed to integrate dopamine pharmacology, cell biology, circuit mechanisms and neuronal processes with behavioral endpoints in animals and patients. State-of-the-art methodologies range from the isolation of novel DRIPs and characterization of their cellular functions in cell cultures through a clinical trial in schizophrenia patients based on a broad array of preclinical research. One subproject interrogates the status of DRIPs in postmortem brains from patients and controls with molecular, neurochemical and anatomical tools. Another subproject examines DA modulation and DA mediated calcium signaling of neural interactions in identified neurons and circuits in PFC cortical slices. Studies of PKA and PKC signaling in rodents, including mice genetically engineered to express DRIPs, are carried out. Other projects will interrogate similar pharmacological as well as physiological mechanisms in nonhuman primates performing cognitive tasks under normal and chronic drug regimens designed to elucidate basic properties of cognitive function and simultaneously parallel the clinical study in Project 9. These multidimensional projects based on novel concepts and discoveries are challenging and risk-taking, but all Pl's have a long record of effective interactions and productive collaboration to justify investment in the potential of this proposal.
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