DESCRIPTION(As provided by Applicant): This project is intended to provide a better understanding of how specific ion channel types regulate the function of mammalian neurons. Such knowledge has been and will continue to be essential for the development of more potent and specific drugs to treat neurological disorders, and will enable scientists to gain a more thorough understanding of congenital diseases resulting from ion channel mutations. The project focuses on a family of ion channels called calcium-activated potassium channels (Kca channels), and on the contribution of this channel family to the function of a well-characterized type of mammalian neuron, the Purkinje neuron of the cerebellum. The project will proceed by addressing the following two specific aims. Aim 1: Determine the contribution of Kca channels to Purkinje neuron excitability. The electrical activity of rat Purkinje neurons will be monitored using the patch clamp technique. KCa channel activity will be manipulated with commercially available blockers and agonists, and the effects on sodium action potentials and dendritic calcium spikes will be assessed. The distribution of KCa channels on the soma and along the dendrite will be estimated using single channel, cell-attached patch recordings. Aim 2: Determine what specific routes of calcium entry activate Kca channels in Purkinje neurons. Electrophysiological methods will be used to examine the consequences of calcium channel blockers on Purkinje cell Kca activity.