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). The results were recently published in the Journal of Clinical Investigation.
With a prevalence of 10-15 % in the general population migraine is one of the most common neurological diseases and is rated as one of the most frequent reasons for years lived with disability. Aside from disease-associated genetic variants in common migraine, there are rare monogenic forms of migraine with aura. Cortical spreading depression (CSD), a wave of depolarization followed by depression of cortical activity, is a pathophysiological process implicated in migraine with aura and various other brain pathologies, such as ischemic stroke and traumatic brain injury. The mechanisms underlying the initiation of CSD and the beginning of a migraine attack as well as the susceptibility to migraine and/or CSD remain elusive. This complicates the development of novel drugs for acute and prophylactic treatment.
To gain insight into the pathophysiology of CSD a team of scientists led by the University of Tübingen and Munich, generated and studied a mouse model for a severe monogenic subtype of migraine with aura, 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 increased Na+-currents leading to hyperactivity of fast-spiking inhibitory interneurons, thus higher susceptibility to cortical spreading depression in vivo. During elicited CSD an increase in extracellular potassium levels in acute brain slices of heterozygous knock-in mice were observed, likely representing the mechanistic link between interneuron hyperactivity and CSD initiation.
As proof of concept, the neuronal phenotype and premature death of homozygous Scn1aL1649Q knock-in mice was partially rescued by GS967, a blocker of persistent Na+-currents. The novel findings identify interneuron hyperactivity as a mechanism to trigger CSD. The knowledge of this mechanism may be relevant for not only migraine research but also for other frequent disorders as ischemic stroke, cerebral hemorrhage, and traumatic brain injury.
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. Epub ahead of print. PMID: 34546973.