iFGF14 Regulation of Cerebellar Neuron Excitability

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 DESCRIPTION (provided by applicant): Intracellular Fibroblast Growth Factor 14 (iFGF14) is a novel accessory subunit of voltage gated sodium (Nav) channels9-11 that is linked to spinal cerebellar ataxia 27 (SCA27)3, a debilitating disease, associated with progressive ataxia and mental decline. Previous work in cultured neurons and heterologous expression systems demonstrate that iFGF14 binds to the C-termini of Nav channel pore forming (α) subunits and modulates the properties of the fast transient Nav currents underlying action potentials5,13. iFGF14 is expressed as two N-terminal splice variants in multiple cell types throughout the central nervous system2,4,5. Deletion or knock-down of iFGF14 has recently been shown to attenuate excitability in cerebellar granule and Purkinje neurons7-8, though, an understanding of how iFGF14 regulates excitability in these cell types or its effect on behavior is lacking. The goa of the proposed research is to determine the effect and role of each iFGF14 splice variant in regulating intrinsic excitability of cerebellar neurons; and, to define how dysfunction of iFGF14 expression in cerebellar neurons can result in deleterious phenotypes. To do this, I will utilize viral vectors for acute expression, or knock-down, of iFGF14 in distinct classes of mouse cerebellar neurons. I will also utilize a newly generated mouse model with a knockin SCA27 causing human mutation FGF14145S. With these experimental systems, I will investigate effects of iFGF14 on Nav currents and intrinsic excitability in cerebellar Purkinje and granule neurons from intact slices. I will complete parallel experiments to define the effects of iFGF14 on mouse balance and motor coordination. The results of the proposed experiments will move our understanding of iFGF14 function forward and provide new insights into the mechanisms underlying SCA27 pathophysiology.