Society for Neuroscience, Journal of Neuroscience, 17(35), p. 6752-6769, 2015
DOI: 10.1523/jneurosci.2663-14.2015
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Mutations inFGF14, which encodes intracellular fibroblast growth factor 14 (iFGF14), have been linked to spinocerebellar ataxia (SCA27). In addition, mice lackingFgf14(Fgf14−/−) exhibit an ataxia phenotype resembling SCA27, accompanied by marked changes in the excitability of cerebellar granule and Purkinje neurons. It is not known, however, whether these phenotypes result from defects in neuronal development or if they reflect a physiological requirement for iFGF14 in the adult cerebellum. Here, we demonstrate that the acute and selectiveFgf14-targeted short hairpin RNA (shRNA)-mediatedin vivo“knock-down” of iFGF14 in adult Purkinje neurons attenuates spontaneous and evoked action potential firing without measurably affecting the expression or localization of voltage-gated Na+(Nav) channels at Purkinje neuron axon initial segments. The selective shRNA-mediatedin vivo“knock-down” of iFGF14 in adult Purkinje neurons also impairs motor coordination and balance. Repetitive firing can be restored inFgf14-targeted shRNA-expressing Purkinje neurons, as well as inFgf14−/−Purkinje neurons, by prior membrane hyperpolarization, suggesting that the iFGF14-mediated regulation of the excitability of mature Purkinje neurons depends on membrane potential. Further experiments revealed that the loss of iFGF14 results in a marked hyperpolarizing shift in the voltage dependence of steady-state inactivation of the Nav currents in adult Purkinje neurons. We also show here that expressing iFGF14 selectively in adultFgf14−/−Purkinje neurons rescues spontaneous firing and improves motor performance. Together, these results demonstrate that iFGF14 is required for spontaneous and evoked action potential firing in adult Purkinje neurons, thereby controlling the output of these cells and the regulation of motor coordination and balance.