Mutated neuronal voltage-gated CaV2.1 channels causing familial hemiplegic migraine 1 increase the susceptibility for cortical spreading depolarization and seizures and worsen outcome after experimental traumatic brain injury
- Ludwig Maximilian University of Munich (LMU), Germany
- Mannheim University, Germany
- Leiden University Medical Center, Netherlands
Abstract
Patients suffering from familial hemiplegic migraine type 1 (FHM1) may have a disproportionally severe outcome after head trauma, but the underlying mechanisms are unclear. Hence, we subjected knock-in mice carrying the severer S218L or milder R192Q FHM1 gain-of-function missense mutation in the CACNA1A gene that encodes the α1A subunit of neuronal voltage-gated CaV2.1 (P/Q-type) calcium channels and their wild-type (WT) littermates to experimental traumatic brain injury (TBI) by controlled cortical impact (CCI) and investigated cortical spreading depolarizations (CSDs), lesion volume, brain edema formation, and functional outcome. After TBI, all mutant mice displayed considerably more CSDs and seizures than WT mice, while S218L mutant mice had a substantially higher mortality. Brain edema formation and the resulting increase in intracranial pressure was more pronounced in mutant mice, while only S218L mutant mice had larger lesion volumes and worse functional outcome. Here we show that gain of CaV2.1 channel function worsens histopathological and functional outcome after TBI in mice. This phenotype was associated with a higher number of CSDs, increased seizure activity, and more pronounced brain edema formation. Hence, our results suggest increased susceptibility for CSDs and seizures as potential mechanisms for bad outcome after TBI in FHM1 mutation carriers.
Data availability
All data generated or analyzed during this study are included in the manuscript. Source Data are available for all figures. A link to a data repository (OSF.io) is provided in the manuscript.
Article and author information
Author details
Nicole A Terpollili
Funding
University of Munich FoeFoLe Program (#669)
- Nicole A Terpollili
Netherlands Organization for Scientific Research (918.56.602)
- Arn MJM van dem Maagdenburg
Centre of Medical System Biology (050-060-409)
- Arn MJM van dem Maagdenburg
European Community (FP7-EUROHEADPAIN)
- Arn MJM van dem Maagdenburg
Deutsche Forschungsgemeinschaft (EXC 2145 SyNergy - ID 390857198)
- Nikolaus Plesnila
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was reviewed by the Ethics Board and approved by the Veterinary Office of the Government of Upper Bavaria (protocol # 118/05). All of the animals were handled according to approved institutional animal care protocols. All surgery was performed in deep inhalation anesthesia and animals received appropriate analgesia post-surgery. Every effort was made to minimize suffering.
Copyright
© 2022, Terpollili et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Mutated neuronal voltage-gated CaV2.1 channels causing familial hemiplegic migraine 1 increase the susceptibility for cortical spreading depolarization and seizures and worsen outcome after experimental traumatic brain injury
eLife 11:e74923.
https://doi.org/10.7554/eLife.74923
