gms | German Medical Science

60th Annual Meeting of the German Society of Neurosurgery (DGNC)
Joint Meeting with the Benelux countries and Bulgaria

German Society of Neurosurgery (DGNC)

24 - 27 May 2009, Münster

Cav2.1 S218L mutant mice reveal increased secondary brain damage after mild traumatic brain injury

Meeting Abstract

  • N. Terpolilli - Klink und Poliklinik für Neurochirurgie, Ludwig-Maximilians-Universität München
  • A. van den Maagdenberg - Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands
  • B. Todorov - Department of Neurology, Leiden University Medical Center, Leiden, the Netherlands
  • M. Ferrari - Department of Neurology, Leiden University Medical Center, Leiden, the Netherlands
  • N. Plesnila - Klink und Poliklinik für Neurochirurgie, Ludwig-Maximilians-Universität München

Deutsche Gesellschaft für Neurochirurgie. 60. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), Joint Meeting mit den Benelux-Ländern und Bulgarien. Münster, 24.-27.05.2009. Düsseldorf: German Medical Science GMS Publishing House; 2009. DocP09-02

DOI: 10.3205/09dgnc342, URN: urn:nbn:de:0183-09dgnc3425

Published: May 20, 2009

© 2009 Terpolilli et al.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc-nd/3.0/deed.en). You are free: to Share – to copy, distribute and transmit the work, provided the original author and source are credited.


Outline

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Objective: About 50% of the patients suffering from Familiar Hemiplegic Migraine have missense mutations in the CACNA1A gene that encodes the pore forming subunit of neuronal voltage-gated Cav2.1 (P/Q-type)Ca2+ channels. CACNA1A FHM mutations lead to a gain of function of Cav2.1 Ca2+ channels. There have been reports that patients with the S218L mutation, in addition to FHM, developed severe brain edema after minor head trauma, often leading to fatal coma. The underlying mechanisms of this overshooting edema formation are not clear yet. Therefore, we generated transgenic knock-in mice carrying the human pathogenic S218L mutation and subjected the mice to experimental traumatic brain injury.

Methods: S218L (heterozygous/homozygous) and wild type mice were subjected to mild controlled cortical impact injury. Animals were allowed to wake up and supervised continuously for seizure activity for 24 hours; after trauma brain edema formation, ICP and lesion size was assessed. Neurological testing was performed using the NSS score before and 24 h after trauma. In a second set of experiments, EEG and DC signals were monitored for 1.5 h after trauma.

Results: Homozygous S218L mice had significantly higher posttraumatic mortality: 60.7% vs. 3.6% (heterozygous) and 0% (wild type mice). Brain water content, ICP and lesion size were increased in the homozygous animals compared to heterozygous and wild type littermates. Furthermore, the homozygous mice performed significantly worse in neurological testing.

Seizure activity was significantly more often observed in homozygotes (4.7 seizures/animal/24h) than in heterozygotes (0.9/animal/24h) or wild type mice (0.1/animal/24h). EEG monitoring showed that the number of posttraumatic cortical spreading depressions (CSDs) over a 90 min recording period was significantly higher in S218L homozygotes (19) than in heterozygotes (9) or wild type mice (1.5). Furthermore, in homozygous mice, CSDs were observed also in the hemisphere contralateral to the trauma; in some cases CSDs were followed by seizure activity.

Conclusions: After trauma mice carrying the human S218L mutation in their Cacna1a gene showed a phenotype similar to that seen in patients: significant edema formation and high mortality after mild head trauma. After traumatic brain injury CSDs occur significantly more often in S218L mice in a dose-dependent manner. This suggests that the increased secondary brain damage seen in patients with the S218L mutation may be caused by CSDs.