Hyperexcitable interneurons trigger cortical spreading depression in an Scn1a migraine model

摘要

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. To gain insight into the pathophysiology of CSD, we generated 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 Na _(V)1.1 predominantly expressed in inhibitory interneurons. Homozygous Scn1a ~(L1649Q) knock-in mice died prematurely, whereas heterozygous mice had a normal lifespan. Heterozygous Scn1a ~(L1649Q) knock-in mice compared with WT mice displayed a significantly enhanced susceptibility to CSD. We found L1649Q to cause a gain-of-function effect with an impaired Na ~(+)-channel inactivation and increased ramp Na ~(+) currents leading to hyperactivity of fast-spiking inhibitory interneurons. Brain slice recordings using K ~(+)-sensitive electrodes revealed an increase in extracellular K ~(+) in the early phase of CSD in heterozygous mice, likely representing the mechanistic link between interneuron hyperactivity and CSD initiation. The neuronal phenotype and premature death of homozygous Scn1a ~(L1649Q) knock-in mice was partially rescued by GS967, a blocker of persistent Na ~(+) currents. Collectively, our findings identify interneuron hyperactivity as a mechanism to trigger CSD.