Dopamine (DA) has a critical influence on the working memory and attention functions of the prefrontal cortex (PFC): Modest levels of D1 receptor stimulation enhance, while high levels impair, PFC cognitive function. The proposed research will provide the first characterization of the intracellular signaling mechanisms underlying these opposing DA actions. Direct infusions into rat PFC will reveal the contributions and interact ons between IP3/calcium signa ing via ca cyon, protein kinase C (PKC) and cAMP/protein kinase A (PKA) mechanisms.
Aim 1 will determine the second messenger mechanisms underlying the cognitive enhancement induced by low doses of D1 receptor agonists, either administered systemically (similar to human subjects in Project 7), or by direct infusion into the rat PFC. We hypothesize that these enhancing effects will be mediated by calcyon/IP3 signaling, possibly amplifying internal calcium release within the dendritic tree and amplifying dendritic integration (see Project 3).
Aim 2 will determine the second messenger mechanisms underlying the cognitive impairment induced by high doses of D1 receptor agonist. Preliminary results suggest that cAMP/PKA signaling mediates the impairment observed at high levels of D1 receptor stimulation, perhaps eroding information transfer from dendrite to soma. We will also test for possible interactions between signaling pathways: eg internal calcium release may potentiate detrimental PKA actions by stimulating adenylyl cyclase isoforms 1 or 8. These studies will explain why high levels of D1 receptor stimulation markedly impair PFC cognitive functioning. Finally, Aim 3 will assess the role of calcyon in PFC cognitive functioning using genetically altered mice created in Project 1. Mice with an overproduction of calcyon will be compared to wildtype controls (and possibly to mice with disabled calcyon). As schizophrenic patients have abnormally high calcyon levels in PFC, the calcyon overexpressing mice will have direct clinical re evance. Mice will be assessed on a battery of PFC vs. control tasks and subsequently tested for their response to D1 agonists. We predict that mice with overexpression of calcyon, similar to schizophrenics will show an exaggerated improvement following low doses of D1 agonists. These studies will provide the first assessment of calcyon's contribution to PFC cognitive function.
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