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The Journal of Neuroscience, June 15, 2003, 23(12):4899-4912
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The Contribution of Resurgent Sodium Current to High-Frequency Firing in Purkinje Neurons: An Experimental and Modeling Study
Zayd M. Khaliq,1 Nathan W. Gouwens,2 andIndira M. Raman1,2,3 1Northwestern University Institute for Neuroscience, 2Integrated Science Program, 3Department of Neurobiology and Physiology, Northwestern University, Evanston, Illinois 60208
Purkinje neurons generate high-frequency action potentials and express voltage-gated, tetrodotoxin-sensitive sodium channels with distinctive kinetics. Their sodium currents activate and inactivate during depolarization, as well as reactivate during repolarization from positive potentials, producing a "resurgent" current. This reopening of channels not only generates inward current after each action potential, but also permits rapid recovery from inactivation, leading to the hypothesis that resurgent current may facilitate high-frequency firing.
Mutant med mice are ataxic and lack expression of the Scn8a gene, which encodes the NaV1.6 protein. In med Purkinje cells, transient sodium current inactivates more rapidly than in wild-type cells, and resurgent current is nearly abolished. To investigate how NaV1.6-specific kinetics influence firing patterns, we recorded action potentials of Purkinje neurons isolated from wild-type and med mice. We also recorded non-sodium currents from Purkinje cells of both genotypes to test whether the Scn8a mutation induced changes in other ion channels. Last, we modeled action potential firing by simulating eight currents directly recorded from Purkinje cells in both wild-type and med mice.
Regular, high-frequency firing was slowed in med Purkinje neurons. In addition to disrupted sodium currents, med neurons had small but significant changes in potassium and leak currents. Simulations indicated that these modified non-sodium currents could not account for the reduced excitability of med cells but instead slightly facilitated spiking. The loss of NaV1.6-specific kinetics, however, slowed simulated spontaneous activity. Together, the data suggest that across a range of conditions, sodium currents with a resurgent component promote and accelerate firing.
Key words: cerebellum; Scn8a; NaV1.6; med; spontaneous firing; K channel; Na channel; NEURON simulation; ataxia
Received Dec. 11, 2002; revised Mar. 28, 2003; accepted Apr. 2, 2003.
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