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.
Metrics
-
- 780
- views
-
- 121
- downloads
-
- 6
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
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
Further reading
-
- Immunology and Inflammation
- Medicine
Together with obesity and type 2 diabetes, metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing global epidemic. Activation of the complement system and infiltration of macrophages has been linked to progression of metabolic liver disease. The role of complement receptors in macrophage activation and recruitment in MASLD remains poorly understood. In human and mouse, C3AR1 in the liver is expressed primarily in Kupffer cells, but is downregulated in humans with MASLD compared to obese controls. To test the role of complement 3a receptor (C3aR1) on macrophages and liver resident macrophages in MASLD, we generated mice deficient in C3aR1 on all macrophages (C3aR1-MφKO) or specifically in liver Kupffer cells (C3aR1-KpKO) and subjected them to a model of metabolic steatotic liver disease. We show that macrophages account for the vast majority of C3ar1 expression in the liver. Overall, C3aR1-MφKO and C3aR1-KpKO mice have similar body weight gain without significant alterations in glucose homeostasis, hepatic steatosis and fibrosis, compared to controls on a MASLD-inducing diet. This study demonstrates that C3aR1 deletion in macrophages or Kupffer cells, the predominant liver cell type expressing C3ar1, has no significant effect on liver steatosis, inflammation or fibrosis in a dietary MASLD model.
-
- Immunology and Inflammation
- Medicine
Background:
Individuals with Down syndrome (DS), the genetic condition caused by trisomy 21 (T21), display clear signs of immune dysregulation, including high rates of autoimmunity and severe complications from infections. Although it is well established that T21 causes increased interferon responses and JAK/STAT signaling, elevated autoantibodies, global immune remodeling, and hypercytokinemia, the interplay between these processes, the clinical manifestations of DS, and potential therapeutic interventions remain ill defined.
Methods:
We report a comprehensive analysis of immune dysregulation at the clinical, cellular, and molecular level in hundreds of individuals with DS, including autoantibody profiling, cytokine analysis, and deep immune mapping. We also report the interim analysis of a Phase II clinical trial investigating the safety and efficacy of the JAK inhibitor tofacitinib through multiple clinical and molecular endpoints.
Results:
We demonstrate multi-organ autoimmunity of pediatric onset concurrent with unexpected autoantibody-phenotype associations in DS. Importantly, constitutive immune remodeling and hypercytokinemia occur from an early age prior to autoimmune diagnoses or autoantibody production. Analysis of the first 10 participants to complete 16 weeks of tofacitinib treatment shows a good safety profile and no serious adverse events. Treatment reduced skin pathology in alopecia areata, psoriasis, and atopic dermatitis, while decreasing interferon scores, cytokine scores, and levels of pathogenic autoantibodies without overt immune suppression.
Conclusions:
JAK inhibition is a valid strategy to treat autoimmune conditions in DS. Additional research is needed to define the effects of JAK inhibition on the broader developmental and clinical hallmarks of DS.
Funding:
NIAMS, Global Down Syndrome Foundation.
Clinical trial number:
