TY - JOUR T1 - Self-Limited Hyperexcitability: Functional Effect of a Familial Hemiplegic Migraine Mutation of the Na<sub>v</sub>1.1 (SCN1A) Na<sup>+</sup> Channel JF - The Journal of Neuroscience JO - J. Neurosci. SP - 7273 LP - 7283 DO - 10.1523/JNEUROSCI.4453-07.2008 VL - 28 IS - 29 AU - Sandrine Cestèle AU - Paolo Scalmani AU - Raffaella Rusconi AU - Benedetta Terragni AU - Silvana Franceschetti AU - Massimo Mantegazza Y1 - 2008/07/16 UR - http://www.jneurosci.org/content/28/29/7273.abstract N2 - 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 Nav1.1 Na+ channel α subunit, but functional studies have been done using the cardiac Nav1.5 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 Nav1.1. 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. ER -