The cellular basis of Episodic Ataxia/Myokemia type1

Oregon Health & Science University, Portland OR

Investigators

Abstract

[unreadable] DESCRIPTION (provided by applicant): The overall goal of this proposal is to determine how a missense mutation in the voltage-gated potassium channel subunit, Kv1.1 alters cerebellar out-put and results in Episodic Ataxia type 1 (EA1). V408A is one of the human EA1 mutations, and results in Kv1.1 channels with an unstable open state. We have generated a V408A mouse model of EA1, and find that it recapitulates the key aspects of the disease. Cerebellar Purkinje Cells (PCs) exhibit an intrinsically generated, tonic firing pattern that is modified by their inhibitory and excitatory inputs. Cerebellar Basket Cells (BCs) express Kv1.1 in their presynaptic terminals, and are the main source of inhibition to PCs. PCs in EA1 mice receive increased GABAergic transmission from BCs. I have found that this increase in GABAergic tone reduces the precision of the interspike interval of PC firing, which is critical for motor control. This PC firing precision deficit is a characteristic of other cerebellar ataxias. This difference is equalized by the GABAAR antagonist picrotoxin (PTX), indicating the importance of increased GABAergic tone in the disease model. For this reason, I propose to investigate the cellular mechanism by which V408A increases GABAergic transmission from BCs to PCs. I will use a combination of 2-photon Ca2+ imaging and electrophysiology to determine whether V408A increases action potential invasion throughout the large presynaptic terminals of BCs. I will assess the possibility that reduced Kv1.1 function increases probability of release for action potential-evoked events. I will additionally use paired-recordings of BC action potentials and PC IPSCs to determine percent failure of AP-induced GABA release. Accomplishing this aim will contribute to our understanding of the physiological role of K+ channels in the presynaptic control of neurotransmitter release, as well as its involvement in the pathophysiology of EA1. The proposed studies will engender novel insights into the cellular mechanisms responsible for a cerebellar ataxia, and may be applicable to additional ataxias. [unreadable] [unreadable] [unreadable]