Pyramidal neurons receive tens of thousands of excitatory and inhibitory synaptic inputs onto their dendrites. The dendrites dynamically alter the strengths of these synapses and coordinate them to produce an output in ways that are not well understood. In previous work we found that there is a very high density of transient, IA-type K+ channels in dendrites of hippocampal CA1 pyramidal neurons. These channels prevent action potential initiation in the dendrites, limit the back-propagation of action potentials into the dendrites, and reduce the amplitudes of excitatory synaptic events. The channels thus exert a powerful control over the overall excitability of these neurons. In studies during the previous funding period, we found that the activity of these channels is decreased by at least two prominent 2nd messenger systems, PKA and PKC, and that these pathways act upstream of MAPK. Furthermore, we have preliminary evidence that CaMKII regulates the expression of A-channels. Additional work during the previous grant suggests that A-channels play a role in both the induction and expression of synaptic plasticity, and that changes in these channels may underlie aspects of the hyperexcitability of epilepsy. The overall objective of this renewal application is to continue to explore the regulation of native A-channels by neurotransmitters and 2nd messengers and to investigate the mechanisms for possible changes in these channels during long-term potentiation (LTP). We will also explore changes in dendritic A-channels and h-channels in an acute model for temporal lobe epilepsy.
The specific aims are: 1) to test the hypothesis that A-type K+ channels in small oblique dendrites are modulated by specific neurotransmitters and 2nd messenger systems; 2) to test the hypothesis that local changes in dendritic excitability during LTP are due to down-regulation of A-channels; 3) to test the hypothesis that the dendritic distribution of A-channels is regulated by CaMKII; and 4) to test the hypothesis that epileptogenesis is due in part to changes in dendritic, voltage-gated channels. The proposed experiments will utilize rat and mouse hippocampal slices, dendritic patch-clamp recordings, and fluorescence imaging. The results of these experiments will provide basic information important for studies of temporal lobe epilepsy, Alzheimer's disease, schizophrenia, and depression.
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