The Role of DPP6 in Kv4 Localization and Dendritic Excitability

DESCRIPTION (provided by applicant): The large diversity of Potassium (K+) channels is a critical determinant to the great variety of electrical properties exhibited by neurons. One such family of potassium channels, the Kv4 family, mediates transient (fast-inactivating) currents which activate at subthreshold membrane potentials and are found in the somatic and dendritic compartments of neurons. This current is referred to as A-type current or ISA in neurons and ITO in the heart. Kv4 channels are thought to be ternary complexes composed of a tetramer of pore forming (Kv4) subunits together with KChIP intracellular auxiliary subunits and DPP-like (DPP6 or DPP10) auxiliary subunits. Kv4 channels have been shown to display complex, dynamic subcellular localization in neurons. This highly specific distribution is crucial to the dendrite's ability to perform several basic functions. These basic signal processing functions include: attenuation of the back propagating action potential, scaling synaptic inputs, modulating individual branch excitability. Kv4 channels are present in a striking gradient along the apical dendrite of hippocampal pyramidal neurons with a higher concentration in the distal dendrite and relatively low perisomatic concentration. This concentration gradient is responsible for the attenuation of the back propagation of the action potential as it invades the dendritic tree, with important consequences for spike-timed dependent synaptic plasticity. It also serves as the signal for proper dendritic scaling along the apical dendrite. However, the molecular determinants of this important gradient are not known. I have been working with DPP6 KO mice to study the role of the auxiliary subunit DPP6 in native neurons, focusing on hippocampal CA1 pyramidal cells. I have obtained exciting preliminary evidence suggesting that DPP6 is necessary for the establishment of the Kv4 channel somato-dendritic gradient. These experiments suggest that the absence of DPP6 causes a redistribution of Kv4 channels including a loss of the somato- dendritic gradient. In this grant I will pursue these preliminary observations to test the hypothesis that DPP6 is an important molecular component of Kv4 channels in neurons that determines its somato-dendritic expression pattern and I will investigate the consequences of DPP6 loss to the cellular and dendritic excitability and generation of synaptic plasticity.