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Subunit Dependence of Na Channel Slow Inactivation and Open Channel Block in Cerebellar Neurons

Interdepartmental Neuroscience Program and Department of Neurobiology and Physiology, Northwestern University, Evanston, Illinois

Correspondence: Address reprint requests to Indira M. Raman, Dept. of Neurobiology and Physiology, 2205 Tech Dr., Northwestern University, Evanston, IL 60208. Tel.: 847-467-7912; Fax: 847-491-5211; E-mail: i-raman{at}northwestern.edu.

Purkinje and cerebellar nuclear neurons both have Na currents with resurgent kinetics. Previous observations, however, suggest that their Na channels differ in their susceptibility to entering long-lived inactivated states. To compare fast inactivation, slow inactivation, and open-channel block, we recorded voltage-clamped, tetrodotoxin-sensitive Na currents in Purkinje and nuclear neurons acutely isolated from mouse cerebellum. In nuclear neurons, recovery from all inactivated states was slower, and open-channel unblock was less voltage-dependent than in Purkinje cells. To test whether specific subunits contributed to this differential stability of inactivation, experiments were repeated in Na_V1.6-null (med) mice. In med Purkinje cells, recovery times were prolonged and the voltage dependence of open-channel block was reduced relative to control cells, suggesting that availability of Na_V1.6 is quickly restored at negative potentials. In med nuclear cells, however, currents were unchanged, suggesting that Na_V1.6 contributes little to wild-type nuclear cells. Extracellular Na⁺ prevented slow inactivation more effectively in Purkinje than in nuclear neurons, consistent with a resilience of Na_V1.6 to slow inactivation. The tendency of nuclear Na channels to inactivate produced a low availability during trains of spike-like depolarization. Hyperpolarizations that approximated synaptic inhibition effectively recovered channels, suggesting that increases in Na channel availability promote rebound firing after inhibition.

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