The central theme of this Program Project application is the role that voltage-gated K/+ channels play in excitability and plasticity of hippocampal pyramidal neurons. A particular type of K/+ channels in the transient, A-type class, has recently been found in high density in dendrites of CA1 pyramidal neurons. These channels exert a profound control over electrical signal propagation and excitability of these neurons, and they appear to be modulated by several second messenger signaling pathways known to be operative in these neurons. Three independent laboratories, each with different by complementary areas of expertise, will combine together in this Program Project to test hypotheses related to the molecular, biochemical and electrophysiological mechanisms for neuromodulation of this K/+ channel, and for the same role that this neuromodulation may play in the excitability and plasticity of these neurons. Some of the questions that will be addressed by these laboratories include: 1) What second messengers and neurotransmitters modulate A channels and neuronal function? 2) What is the native A channel's composition? Is the channel composed of Shal alpha subunits, and Kv4.2 in particular? 3) Are PDZ binding sequences on Shal alpha subunits involved in localizing channels to dendrites? 4) How are channels that are made from Shal Kv4.2 subunits regulated by phosphorylation at different sites? 5) Does the neuromodulation of the native A channel participate in the induction and/or expression of long-term plasticity of hippocampal neurons? 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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