Paul Kelly

Mechanisms that regulate and modify nerve cell interactions.

Intracellular signaling mechanisms regulate synaptic transmission and synaptic plasticity. Mechanisms controlling synaptic transmission are believed to be critical for learning and memory in humans. We are answering key questions about molecular/cellular mechanisms responsible for short- and long-term changes in synaptic transmission in the mammalian brain. We examine the role of postsynaptic calcium, protein kinase and phosphatase pathways in controlling synaptic transmission in the hippocampus, a brain region important for learning in humans. We have discovered many reliable ways to enhance synaptic transmission by specific manipulations of intracellular signaling pathways. We discovered manipulations that enhance synaptic transmission by postsynaptic injections of protein kinase activators or protein phosphatase inhibitors. Injecting calcium/calmodulin into hippocampal neurons substantially enhances synaptic transmission and requires calcium-dependent protein kinase activities. Our results indicate that postsynaptic calcium/calmodulin is a critical rate limiting factor regulating synaptic transmission. We recently discovered that stimulating intracellular calcium release with inositol triphosphate (IP3) receptor agonists potentiates synaptic transmission. IP3 receptor-mediated synaptic potentiation is developmentally regulated, occludes tetanus-induced long-term potentiation and is blocked by inhibitors of calcium/calmodulin kinases, protein kinase C and calcium/calmodulin. Stimulation of IP3 receptor-mediated calcium release induces a fast conversion of inactive-to-active glutamate receptors in postsynaptic hippocampal neurons. Our findings show that synaptic transmission and synaptic plasticity is controlled by functional cross talk and a dynamic balance among specific postsynaptic calcium-dependent protein kinase and phosphatase pathways.