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Hyperexcitable interneurons trigger cortical spreading depression in an Scn1a migraine model
Eva Auffenberg1,2, Ulrike Bs Hedrich1, Raffaella Barbieri3
1Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
The Journal of Clinical Investigation
|September 21, 2021
Summary
Cortical spreading depression (CSD) is linked to migraines and brain injuries. This study shows that hyperactivity in inhibitory interneurons can trigger CSD, offering new insights into brain pathologies.
Area of Science:
- Neuroscience
- Pathophysiology
- Genetics
Background:
- Cortical spreading depression (CSD) is a key process in migraine with aura, stroke, and brain injury.
- Familial hemiplegic migraine type 3 (FHM3) is a severe subtype caused by mutations in SCN1A, which encodes the NaV1.1 sodium channel in inhibitory interneurons.
Purpose of the Study:
- To investigate the role of NaV1.1 channel dysfunction in inhibitory interneurons in CSD pathophysiology.
- To develop and characterize a mouse model for FHM3.
Main Methods:
- Generated heterozygous and homozygous Scn1aL1649Q knock-in mice.
- Performed electrophysiological recordings (in vivo and brain slices) using K+-sensitive electrodes.
- Administered GS967, a persistent Na+ current blocker, to assess rescue effects.
Main Results:
- Heterozygous mice exhibited enhanced susceptibility to CSD.
- The L1649Q mutation caused NaV1.1 gain-of-function, leading to interneuron hyperactivity.
- Increased extracellular K+ during CSD in heterozygous mice was observed, linking interneuron hyperactivity to CSD initiation.
- GS967 partially rescued the phenotype and premature death in homozygous mice.
Conclusions:
- Interneuron hyperactivity is identified as a mechanism that triggers CSD.
- NaV1.1 channel dysfunction in inhibitory interneurons plays a critical role in CSD.
- This mouse model provides a valuable tool for studying FHM3 and related CSD pathologies.
