There is now a significant body of evidence that growth factors and cytokines are involved in neuropathological and psychiatric disorders; precisely how these effects are mediated is unknown. Insulin and other growth factors are well known to modulate metabolism and differentiation/proliferation, respectively. However, on differentiated neurons, the major role of insulin and cytokines may be, to modulate neurotransmission. A necessary prerequisite for understanding growth factor/cytokine actions is to identify the molecular mechanisms by which these factors exert their biological action on neurons. The objective of this proposal is to determine the signal transduction pathway and, molecular mechanisms by which a growth factor (insulin) regulates synaptic transmission (potentiation of NMDA receptor activity)This model system was chosen because it has significant neuropathological and psychiatric implications. NMDA receptors are thought to play a key role various diseases (e.g. AIDS dementia, epilepsy, stroke, schizophrenia, ALS, and others), thus factors that regulate them may contribute to neurological and psychiatric disorders, and thus account for the observations that insulin improves symptoms in both Alzheimer's disease and schizophrenia. Our specific experimental goals are: 1) to use pharmacological agents and electrophysiological techniques to identify the receptor type and signal transduction pathways that mediate insulin potentiation of NMDA receptor responses in rat hippocampal slices and in Xenoptis oocytes expressing recombinant NMDA receptors; 2) to use mutated recombinant insulin receptors and insulin receptor substrates (IRS-1) to identify which signaling components of the insulin receptor system initiatee modulation of NMDA receptor responses; 3) to identify the insulin-induced phosphorylation (or dephosphorylation) sites on rat hippocampal NMDA receptors and then use site-directed mutagenesis to determine the role of these phosphorylation sites on NMDA receptor function in Xenopus oocytes. Together these studies win identify the specific cellular signaling pathways and molecular mechanisms by which insulin modulates NMDA receptor activity. This knowledge would serve as a basis for determining insulin's role in several aspects of brain function and neurological disorders. These studies would also generate predictions about which other growth factor / cytokine systems mediate similar effects and would generate markers that could test the role of this signaling system in neurological and psychiatric disorders.
