Abstract
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 NaV1.1 predominantly expressed in inhibitory interneurons. Homozygous Scn1aL1649Q knock-in mice died prematurely, whereas heterozygous mice had a normal lifespan. Heterozygous Scn1aL1649Q 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 Scn1aL1649Q 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.
Highlights
With a prevalence of 10% to 15% in the general population, migraine is one of the most common neurological diseases [1, 2] and is rated as one of the most frequent reasons for years lived with disability [3]
As expected for a gain-of-function Na+-channel mutation increasing neuronal firing in interneurons, we observed a significantly increased frequency of spontaneous inhibitory postsynaptic currents (IPSCs) in heterozygous animals versus WT littermates (Figure 4, E–G)
Our results demonstrate a mechanism for cortical spreading depression (CSD) and migraine, as exemplified in a mouse model of familial hemiplegic migraine type 3 (FHM3)
Summary
With a prevalence of 10% to 15% in the general population, migraine is one of the most common neurological diseases [1, 2] and is rated as one of the most frequent reasons for years lived with disability [3]. 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. Aside from disease-associated genetic variants in common migraine [8], there are rare monogenic forms of migraine with aura. SCN1A encodes the alpha subunit of a voltage-gated sodium channel (NaV1.1), which is mainly expressed and functionally important in inhibitory GABAergic interneurons [15,16,17,18,19].
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