期刊
JOURNAL OF NEUROSCIENCE
卷 23, 期 12, 页码 4899-4912出版社
SOC NEUROSCIENCE
DOI: 10.1523/jneurosci.23-12-04899.2003
关键词
cerebellum; Scn8a; Na(V)1.6; med; spontaneous firing; K channel; Na channel; NEURON simulation; ataxia
资金
- NINDS NIH HHS [R56 NS039395, R01 NS039395, NS39395, T32 NS041234, R37 NS039395, 5T32 NS41234] Funding Source: Medline
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 Na(V)1.6 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 Na(V)1.6-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 Na(V)1.6-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.
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