Loss of Navβ4-Mediated Regulation of Sodium Currents in Adult Purkinje Neurons Disrupts Firing and Impairs Motor Coordination and Balance

Joseph L. Ransdell, Edward Dranoff, Brandon Lau, Wan Lin Lo, David L. Donermeyer, Paul M. Allen, Jeanne M. Nerbonne

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

The resurgent component of voltage-gated Na+ (Nav) currents, INaR, has been suggested to provide the depolarizing drive for high-frequency firing and to be generated by voltage-dependent Nav channel block (at depolarized potentials) and unblock (at hyperpolarized potentials) by the accessory Navβ4 subunit. To test these hypotheses, we examined the effects of the targeted deletion of Scn4b (Navβ4) on INaR and on repetitive firing in cerebellar Purkinje neurons. We show here that Scn4b−/− animals have deficits in motor coordination and balance and that firing rates in Scn4b−/− Purkinje neurons are markedly attenuated. Acute, in vivo short hairpin RNA (shRNA)-mediated “knockdown” of Navβ4 in adult Purkinje neurons also reduced spontaneous and evoked firing rates. Dynamic clamp-mediated addition of INaR partially rescued firing in Scn4b−/− Purkinje neurons. Voltage-clamp experiments revealed that INaR was reduced (by ∼50%), but not eliminated, in Scn4b−/− Purkinje neurons, revealing that additional mechanisms contribute to generation of INaR.

Original languageEnglish
Pages (from-to)532-544
Number of pages13
JournalCell Reports
Volume19
Issue number3
DOIs
StatePublished - Apr 18 2017

Keywords

  • Scn4b
  • Scn4b-targeted shRNA
  • cerebellum
  • dynamic clamp
  • resurgent sodium current

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