CaV2.1 channel mutations causing familial hemiplegic migraine type 1 increase the susceptibility for cortical spreading depolarizations and seizures and worsen outcome after experimental traumatic brain injury
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Curated by eLife
Evaluation Summary:
The authors demonstrate that patients carrying a gain-of-function S218L mutation in CACNA1A exhibit a gene-dosage-dependent increase in the susceptibility to cortical spreading depression (CSD), seizure activity and brain edema formation following TBI compared with wild-type (WT) mice or mice carrying the milder R192Q mutation. This paper will be of considerable interest to familial hemiplegic migraine (FHM) sufferers who experience traumatic brain injury (and their physicians), as well researchers with an interest in the spectrum and phenotypic consequences of mutations in the voltage-gated, P/Q-type Ca2+ channel, CACNA1A.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)
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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 α 1A subunit of neuronal voltage-gated Ca V 2.1 (P/Q-type) calcium channels and their wild-type (WT) littermates to experimental traumatic brain injury (TBI) by controlled cortical impact 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 were more pronounced in mutant mice, while only S218L mutant mice had larger lesion volumes and worse functional outcome. Here, we show that gain of Ca V 2.1 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.
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Evaluation Summary:
The authors demonstrate that patients carrying a gain-of-function S218L mutation in CACNA1A exhibit a gene-dosage-dependent increase in the susceptibility to cortical spreading depression (CSD), seizure activity and brain edema formation following TBI compared with wild-type (WT) mice or mice carrying the milder R192Q mutation. This paper will be of considerable interest to familial hemiplegic migraine (FHM) sufferers who experience traumatic brain injury (and their physicians), as well researchers with an interest in the spectrum and phenotypic consequences of mutations in the voltage-gated, P/Q-type Ca2+ channel, CACNA1A.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers …
Evaluation Summary:
The authors demonstrate that patients carrying a gain-of-function S218L mutation in CACNA1A exhibit a gene-dosage-dependent increase in the susceptibility to cortical spreading depression (CSD), seizure activity and brain edema formation following TBI compared with wild-type (WT) mice or mice carrying the milder R192Q mutation. This paper will be of considerable interest to familial hemiplegic migraine (FHM) sufferers who experience traumatic brain injury (and their physicians), as well researchers with an interest in the spectrum and phenotypic consequences of mutations in the voltage-gated, P/Q-type Ca2+ channel, CACNA1A.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)
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Joint Public Review:
The study "Mutated neuronal voltage-gated CaV2.1 channels causing familial hemiplegic 4 migraine 1 increase the susceptibility for cortical spreading depolarization 5 and seizures and worsen outcome after experimental traumatic brain injury" describes a higher susceptibility and number of cortical spreading depressions in mice bearing the S218L and R192Q mutations following experimental TBI induced by CCI. Increased number of CSD´S is associated with a slight increase in lesion size and edema. Moreover, a higher mortality was experienced in S218L transgenic mice. The study has been well conducted, the experimental procedures are well described.
The study provides the first essential step in understanding the higher susceptibility of mice with respective mutations to acute brain injury. Further subsequent …
Joint Public Review:
The study "Mutated neuronal voltage-gated CaV2.1 channels causing familial hemiplegic 4 migraine 1 increase the susceptibility for cortical spreading depolarization 5 and seizures and worsen outcome after experimental traumatic brain injury" describes a higher susceptibility and number of cortical spreading depressions in mice bearing the S218L and R192Q mutations following experimental TBI induced by CCI. Increased number of CSD´S is associated with a slight increase in lesion size and edema. Moreover, a higher mortality was experienced in S218L transgenic mice. The study has been well conducted, the experimental procedures are well described.
The study provides the first essential step in understanding the higher susceptibility of mice with respective mutations to acute brain injury. Further subsequent investigations will be required to unravel underlying cellular and subcellular mechanisms.
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