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The Journal of Neuroscience, July 16, 2008, 28(29):7273-7283; doi:10.1523/JNEUROSCI.4453-07.2008

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Neurobiology of Disease
Self-Limited Hyperexcitability: Functional Effect of a Familial Hemiplegic Migraine Mutation of the Na_v1.1 (SCN1A) Na⁺ Channel

Sandrine Cestèle,^1,2 Paolo Scalmani,¹ Raffaella Rusconi,¹ Benedetta Terragni,¹ Silvana Franceschetti,¹ and Massimo Mantegazza^1,3

¹Department of Neurophysiopathology, Besta Neurological Institute, 20133 Milan, Italy, ²Inserm U836 (Equipe 3), Institute of Neurosciences, 38054 Grenoble, France, and ³Equipe Avenir Inserm, Institut Fédératif de Recherche 95-Saints-Pères, Université Paris 5–Descartes, 75006 Paris, France

Correspondence should be addressed to Dr. Massimo Mantegazza, Department of Neurophysiopathology, Besta Neurological Institute, Via Celoria 11, 20133 Milan, Italy. Email: mmantegazza{at}istituto-besta.it

Familial hemiplegic migraine (FHM) is an autosomal dominant inherited subtype of severe migraine with aura. Mutations causing FHM (type 3) have been identified in SCN1A, the gene encoding neuronal voltage-gated Na_v1.1 Na⁺ channel subunit, but functional studies have been done using the cardiac Na_v1.5 isoform, and the observed effects were similar to those of some epileptogenic mutations. We studied the FHM mutation Q1489K by transfecting tsA-201 cells and cultured neurons with human Na_v1.1. We show that the mutation has effects on the gating properties of the channel that can be consistent with both hyperexcitability and hypoexcitability. Simulation of neuronal firing and long depolarizing pulses mimicking promigraine conditions revealed that the effect of the mutation is a gain of function consistent with increased neuronal firing. However, during high-frequency discharges and long depolarizations, the effect became a loss of function. Recordings of firing of transfected neurons showed higher firing frequency at the beginning of long discharges. This self-limited capacity to induce neuronal hyperexcitability may be a specific characteristic of migraine mutations, able to both trigger the cascade of events that leads to migraine and counteract the development of extreme hyperexcitability typical of epileptic seizures. Thus, we found a possible difference in the functional effects of FHM and familial epilepsy mutations of Nav1.1.

Key words: migraine; current; epilepsy; excitability; neuron; sodium channel

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Received Sept. 28, 2007; revised May 23, 2008; accepted May 27, 2008.

Correspondence should be addressed to Dr. Massimo Mantegazza, Department of Neurophysiopathology, Besta Neurological Institute, Via Celoria 11, 20133 Milan, Italy. Email: mmantegazza{at}istituto-besta.it

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