Journal
JOURNAL OF NEUROSCIENCE
Volume 35, Issue 17, Pages 6752-6769Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.2663-14.2015
Keywords
channel inactivation; FGF14; fibroblast growth factor homologous factor 4 (FHF4); intrinsic excitability; spinocerebellar ataxia 27; voltage-gated sodium (Nav) channels
Categories
Funding
- National Institutes of Health [R01NS065761, T32 GM007200, T32 HL007275, U24NS050606]
- Genome Institute
- Children's Discovery Institute [CDI-LI-2010-94]
- Neuroscience Blueprint Core [P30 NS057105]
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Mutations in FGF14, which encodes intracellular fibroblast growth factor 14 (iFGF14), have been linked to spinocerebellar ataxia (SCA27). In addition, mice lacking Fgf14 (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 selective Fgf14-targeted short hairpin RNA (shRNA)-mediated in 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-mediated in vivo knock-down of iFGF14 in adult Purkinje neurons also impairs motor coordination and balance. Repetitive firing can be restored in Fgf14-targeted shRNA-expressing Purkinje neurons, as well as in Fgf14(-/-) 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 adult Fgf14(-/-) 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.
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