Voltage-gated ion channels and synaptic integration by cerebellar Purkinje cells

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DESCRIPTION (provided by applicant): The role of voltage-gated channels in shaping synaptic integration in cerebellar Purkinje cells is little understood. Examination of their functional properties and interactions is of critical interest since many debilitating hereditary diseases presenting cerebellar symptoms, including episodic ataxia types 1 (EA1) and 2 (EA2), and spinocerebellar ataxia type 6 (SCA6), are disorders of these membrane proteins. The overall goal of this research plan is to define the contributions of select voltage-gated conductances to the integration of excitatory synaptic inputs by Purkinje cells. Purkinje cells integrate a massive convergence of excitatory and inhibitory inputs and are the sole output of the cerebellar cortex. They are thus the main computational units of the cerebellum, ultimately enabling proper motor coordination, posture, and balance. Prior work in the lab established that Purkinje cells linearly encode the strength of their presynaptic glutamatergic granule cell inputs in their maximum post-stimulus firing rate. This was surprising considering that Purkinje cells exhibit active dendritic calcium spikes brought about by various dendritic voltage-gated conductances, which are inherently nonlinear. How is the activity of voltage-gated channels in Purkinje cells choreographed to allow for the linear summation of their granule cell inputs? We propose two aims to begin answering this question: 1) To noninvasively assess the contribution of select voltage-gated ion channels to the granule cell input-Purkinje cell output function; and 2) To test the hypothesis that active dendritic conductances are balanced to achieve the linear granule cell input-Purkinje cell output relationship. We will accomplish this through experiments combining extracellular and whole-cell patch clamp electrophysiology, glutamate uncaging, and pharmacology applied to a rat cerebellar slice preparation. These investigations are not only crucial to understanding neural control of movement and the mechanisms underlying ataxia, but also will help elucidate neuronal computational processes in general.