The central theme of this Program Project Grant is the role that voltage-gated, A-type K+ channels play in excitability and plasticity of hippocampal CA1 pyramidal neurons. These channels are expressed in high density in the dendrites of these cells and exert profound control over electrical signal propagation and excitability. They are also modulated by several well-known second messenger signaling pathways and certain newly-described interacting proteins. Three independent laboratories, each with different but complementary areas of expertise (biochemistry, molecular biology, physiology) have come together in this Program Project to test hypotheses related to the molecular, biochemical, and electrophysiological mechanisms for regulation of this K+ channel and its putative subunit Kv4.2, and for the role that this regulation may play in the excitability and plasticity of these neurons. Significant progress has been made during the previous funding period in understanding the biochemistry and physiology of neuromodulation of Kv4.2 and native A-currents. Moreover, interesting recent evidence has been obtained regarding a potential mechanism for the dendritic expression of Kv4.2 and for changes in dendritic A-channels associated with LTP and epileptogenesis. We propose to continue these studies during the next funding period. Principal questions to be addressed include: 1) What are the mechanisms for local increases in dendritic excitability during LTP? 2) Does CaMKII regulate expression of native A-channels in dendrites and what are the mechanisms? 3) What are the structure-function relationships among interacting proteins, modulatory protein kinases, and Kv4.2? 4) What are the regulatory proteins that interact with Kv4.2 and do they operate in situ? 5) Are there changes in dendritic, voltage-gated channels that are responsible for hyperexcitability during epilepsy? Because the hippocampus has a low seizure threshold and plays a critical role in learning and memory and other higher cognitive processes, the results of these studies will provide important basic information for a better understanding of temporal lobe epilepsy, Alzheimer's Disease, schizophrenia, and depression.
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