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

The resurgent component of voltage-gated Na⁺ (Nav) currents, I_NaR, 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 I_NaR 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 I_NaR partially rescued firing in Scn4b^-/- Purkinje neurons. Voltage-clamp experiments revealed that I_NaR was reduced (by ∼50%), but not eliminated, in Scn4b^-/- Purkinje neurons, revealing that additional mechanisms contribute to generation of I_NaR.

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