AXONAL PROPAGATION FAILURE AND AXON INITIAL SEGMENT DISORGANIZATION IN THE PURKINJE CELLS OF A MOUSE MODEL OF ARSACS

Autosomal recessive spastic ataxia of the Charlevoix-Saguenay region (ARSACS) is an inherited ataxia prevalent in Quebec. Studies of a mouse model of ARSACS in which the gene Sacs has been knocked out (ARSACS mice) show that cerebellar Purkinje cells exhibit changes, including in axonal morphology. We explored axonal function in ARSACS using ARSACS and wild-type littermates (WT) mice. Using 2-photon targeted simultaneous dual electrophysiological recordings from the soma and axon of Purkinje cells expressing GFP, we measured the fidelity of propagation of action potentials. Action potential propagation in ARSACS axons was profoundly impaired at disease onset (~p40), when motor deficits are mild. While failures were low in WT axons (<1% of action potentials failed), in ARSACS mice axonal failures were high: an average of 15% of action potentials fail (**p<0.01). In many cases, action potential propagation failure increased steeply with distances from the soma – often to >90% – suggesting that axonal propagation is passive rather than active in ARSACS axons. We investigated factors that might contribute to axonal impairment and found evidence of disorganization of scaffolding molecules within the axon initial segment (AIS). Given the severity with which Purkinje cell action potential propagation is affected early in disease progression, our results suggest that axonal dysfunction is an important contributor to ARSACS pathology, and thus could be a vital target for treating ARSACS, and possibly other neurodegenerative diseases as well.