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The dendrites of CA1 pyramidal neurons receive and process tens of thousands of excitatory and inhibitory inputs in ways that are not well understood. The presence of voltage-gated channels (active dendrites) suggests that computations are performed in dendrites, subsequent to synaptic input. Although much current and past research on synaptic plasticity in CA1 pyramidal neurons has focused on glutamate receptor regulation, relatively little is known about how voltage-gated channels influence synaptic integration. Combining patch clamp recording with imaging and molecular biology techniques, our research plan is to investigate the electrophysiological properties and molecular nature of the voltage-gated channels expressed in hippocampal dendrites. Our long-term goal is to investigate how these channels are regulated, what role they play in learning and memory and how their malfunction contributes to diseases of the hippocampus such as Alzheimer's disease and epilepsy.
Figure 1. Time-lapse images showing Kv4.2g fluorescent intensity decrease upon AMPA (50 ?M) stimulation in spines of hippocampal neurons co-expressing Kv4.2g and tdTomato.
To date we have focused our efforts on a particular somatodendritic voltage-gated potassium channel subunit, Kv4.2. Kv4.2 is highly expressed in CA1 dendrites and is the molecular identity of the subthreshold, rapidly inactivating (A-type) potassium current that has been shown to influence CA1 dendritic signal propagation. The large density of dendritic Kv4.2 channels acts to shape incoming synaptic signals and limit action potential backpropagation into dendrites. To assess the role of Kv4.2 channels in regulating CA1 firing properties, synaptic integration and synaptic plasticity, we have developed the means to alter functional Kv4.2 expression in cultured hippocampal neurons, in organotypic hippocampal slice cultures, and in mice. Using these tools, we have found that dendritic Kv4.2 surface expression is regulated in an activity-dependent manner, providing a new means by which Kv4.2 channels may influence synaptic function. We have also begun to characterize the mechanisms of activity dependent Kv4.2 trafficking, Kv4.2's affect on synaptic plasticity and the role of Kv4.2 auxiliary subunits in these processes.