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The Journal of Neuroscience, October 25, 2006, 26(43):10958-10966; doi:10.1523/JNEUROSCI.3378-06.2006

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Neurobiology of Disease
Impaired Inactivation Gate Stabilization Predicts Increased Persistent Current for an Epilepsy-Associated SCN1A Mutation

Kristopher M. Kahlig,¹ Sunita N. Misra,² and Alfred L. George, Jr^1,2

¹Division of Genetic Medicine, Department of Medicine, and ²Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232-0275

Correspondence should be addressed to Dr. Alfred L. George Jr, Division of Genetic Medicine, 529 Light Hall, Vanderbilt University, 2215 Garland Avenue, Nashville, TN 37232-0275. Email: al.george{at}vanderbilt.edu

Mutations in SCN1A (encoding the neuronal voltage-gated sodium channel ₁ subunit, Na_V1.1, or SCN1A) are associated with genetic epilepsy syndromes including generalized epilepsy with febrile seizures plus (GEFS+) and severe myoclonic epilepsy of infancy. Here, we present the formulation and use of a computational model for SCN1A to elucidate molecular mechanisms underlying the increased persistent sodium current exhibited by the GEFS+ mutant R1648H. Our model accurately reproduces all experimentally measured SCN1A whole-cell biophysical properties including biphasic whole-cell current decay, channel activation, and entry into and recovery from fast and slow inactivation. The model predicts that SCN1A open-state inactivation results from a two-step process that can be conceptualized as initial gate closure, followed by recruitment of a mechanism ("latch") to stabilize the inactivated state. Selective impairment of the second latching step results in an increase in whole-cell persistent current similar to that observed for the GEFS+ mutant R1648H. These results provide a deeper level of understanding of mutant SCN1A dysfunction in an inherited epilepsy syndrome, which will enable more precise computational studies of abnormal neuronal activity in epilepsy and may help guide new targeted therapeutic strategies.

Key words: sodium channel; GEFS+; Markov model; SCN1A; epilepsy; computational neuroscience

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Received June 6, 2006; revised Sept. 11, 2006; accepted Sept. 11, 2006.

Correspondence should be addressed to Dr. Alfred L. George Jr, Division of Genetic Medicine, 529 Light Hall, Vanderbilt University, 2215 Garland Avenue, Nashville, TN 37232-0275. Email: al.george{at}vanderbilt.edu

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