Pathophysiology of familial hemiplegic migraine: analysis of a newly generated transgenic SCN1A mouse model

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Familial hemiplegic migraine (FHM) is a severe autosomal-dominant subtype of migraine with aura. The applicants, by means of positional cloning, have identified SCN1A as the third FHM gene (FHM3; Dichgans*, Freilinger* et al. Lancet 2005). SCN1A encodes a neuronal voltage-gated sodium channel (Nav1.1), which is responsible for the generation and propagation of action potentials.Previous studies in cells overexpressing Nav1.1 channels with FHM-associated mutations point towards a loss-of-function of mutant channels in FHM patients (Kahlig, ..., Freilinger et al. Proc Natl Acad Sci U S A 2008). However, the precise role of mutant NaV1.1 for migraine and migraine aura remains unclear to date.To unravel the significance of NaV1.1 in the pathophysiology of migraine and migraine aura, the applicants, by means of homologous recombination, have generated a knock-in mouse model for a representative human SCN1A mutation (L1649Q).After an initial characterization of transgenic animals with respect to biochemistry and histology, the following specific hypotheses will be tested in this newly generated animal model: 1.) Scn1a knock-in animals show episodic neurological disturbances (e.g. hemiplegic attacks or epileptic seizures).2.) Scn1a knock-in animals have an increased susceptibility to the induction of cortical spreading depolarisations (CSD), the likely correlate of migraine aura.3.) Scn1a knock-in animals have neurophysiological alterations, which can explain neuronal hyperexcitability.In detail, the following investigations are planned: 1.) multimodal functional characterization of Scn1aL1649Q KI animals, focussing specifically on migraine equivalents and epileptic seizures, 2.) analysis of the effects of the mutation on experimentally induced CSD in vivo, 3.) electrophysiological characterization of the mutation in primary neuronal cell cultures from Scn1aL1649Q KI animals complemented by an analysis of acute brain slices and spontaneous neuronal network activity.By means of these investigations, we hope to gain further insight into the pathophysiology of FHM and migraine in general, which may open the door for the development of novel therapeutic strategies.Of note, mutations in Scn1a are associated also with epilepsy. We have access to a transgenic epilepsy mouse model carrying a mutation of the amino acid immediately adjacent to L1649 (R1648H). This will allow a direct head-to-head comparison of these two animal models, aiming at a better understanding of the differential mechanisms of migraine and epilepsy, i.e. two phenotypically overlapping paroxysmal neurological disorders.