Insights in the genesis of migraine

In this current study scientists teamed up to unraveled the mechanistic cascade underlying cortical spreading depression (CSD) and migraine susceptibility exemplified in a mouse model of familial hemiplegic migraine type 3 (FHM3).

FHM3 is caused by mutations in SCN1A, encoding the voltage-gated Na+ channel NaV1.1 predominantly expressed in inhibitory interneurons. Homozygous Scn1aL1649Q knock-in mice died prematurely, whereas heterozygous mice had a normal lifespan, but displayed a significantly enhanced susceptibility to CSD. The researchers found out, that the Scn1aL1649Q variant caused a gain-of-function effect with an impaired Na+-channel inactivation and identified hyperactivity of fast-spiking inhibitory interneurons as a mechanism to trigger CSD.

Auffenberg E, Hedrich UB, Barbieri R, Miely D, Groschup B, Wuttke TV, Vogel N, Lührs P, Zanardi I, Bertelli S, Spielmann N, Gailus-Durner V, Fuchs H, Hrabě de Angelis M, Pusch M, Dichgans M, Lerche H, Gavazzo P, Plesnila N, Freilinger T. Hyperexcitable interneurons trigger cortical spreading depression in an Scn1a migraine model. J Clin Invest. 2021 Sep 21:e142202. doi: 10.1172/JCI142202.