Fibroblast Growth Factor Homologous Factors Control Neuronal Excitability through Modulation of Voltage-Gated Sodium Channels

Mitchell Goldfarb, Jon Schoorlemmer, Anthony Williams, Shyam Diwakar, Qing Wang, Xiao Huang, Joanna Giza, Dafna Tchetchik, Kevin Kelley, Ana Vega, Gary Matthews, Paola Rossi, David M. Ornitz, Egidio D'Angelo

Research output: Contribution to journalArticle

Abstract

Neurons integrate and encode complex synaptic inputs into action potential outputs through a process termed "intrinsic excitability." Here, we report the essential contribution of fibroblast growth factor homologous factors (FHFs), a family of voltage-gated sodium channel binding proteins, to this process. Fhf1-/-Fhf4-/- mice suffer from severe ataxia and other neurological deficits. In mouse cerebellar slice recordings, WT granule neurons can be induced to fire action potentials repetitively (∼60 Hz), whereas Fhf1-/-Fhf4-/- neurons often fire only once and at an elevated voltage spike threshold. Sodium channels in Fhf1-/-Fhf4-/- granule neurons inactivate at more negative membrane potential, inactivate more rapidly, and are slower to recover from the inactivated state. Altered sodium channel physiology is sufficient to explain excitation deficits, as tested in a granule cell computer model. These findings offer a physiological mechanism underlying human spinocerebellar ataxia induced by Fhf4 mutation and suggest a broad role for FHFs in the control of excitability throughout the CNS.

Original languageEnglish
Pages (from-to)449-463
Number of pages15
JournalNeuron
Volume55
Issue number3
DOIs
Publication statusPublished - Aug 2 2007

Keywords

  • MOLNEURO
  • SIGNALING

ASJC Scopus subject areas

  • Neuroscience(all)

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    Goldfarb, M., Schoorlemmer, J., Williams, A., Diwakar, S., Wang, Q., Huang, X., Giza, J., Tchetchik, D., Kelley, K., Vega, A., Matthews, G., Rossi, P., Ornitz, D. M., & D'Angelo, E. (2007). Fibroblast Growth Factor Homologous Factors Control Neuronal Excitability through Modulation of Voltage-Gated Sodium Channels. Neuron, 55(3), 449-463. https://doi.org/10.1016/j.neuron.2007.07.006