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Hyperexcitable interneurons trigger cortical spreading depression in an Scn1a migraine model
- Source :
- Journal of Clinical Investigation. November 1, 2021, Vol. 131 Issue 21
- Publication Year :
- 2021
-
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.sup.+] channel [Na.sub.V]1.1 predominantly expressed in inhibitory interneurons. Homozygous [Scn1a.sup.L1649Q] knock-in mice died prematurely, whereas heterozygous mice had a normal lifespan. Heterozygous [Scn1a.sup.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.sup.+]*-channel inactivation and increased ramp [Na.sup.+] currents leading to hyperactivity of fast-spiking inhibitory interneurons. Brain slice recordings using [K.sup.+]-sensitive electrodes revealed an increase in extracellular [K.sup.+] 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.sup.L1649Q] knock-in mice was partially rescued by GS967, a blocker of persistent [Na.sup.+] currents. Collectively, our findings identify interneuron hyperactivity as a mechanism to trigger CSD.<br />Introduction 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 [...]
Details
- Language :
- English
- ISSN :
- 00219738
- Volume :
- 131
- Issue :
- 21
- Database :
- Gale General OneFile
- Journal :
- Journal of Clinical Investigation
- Publication Type :
- Academic Journal
- Accession number :
- edsgcl.682076190
- Full Text :
- https://doi.org/10.1172/JCI142202