Spontaneous and optogenetically induced cortical spreading depolarization in familial hemiplegic migraine type 1 mutant mice

Neurobiology of Disease, vol. 192, pp. 106405

Abstract

Mechanisms underlying the migraine aura are incompletely understood, which to large extent is related to a lack of models in which cortical spreading depolarization (CSD), the correlate of the aura, occurs spontaneously. Here, we investigated electrophysiological and behavioural CSD features in freely behaving mice expressing mutant CaV2.1 Ca2+ channels, either with the milder R192Q or the severer S218L missense mutation in the α1 subunit, known to cause familial hemiplegic migraine type 1 (FHM1) in patients. Very rarely, spontaneous CSDs were observed in mutant but never in wildtype mice. In homozygous Cacna1aR192Q mice exclusively single-wave CSDs were observed whereas heterozygous Cacna1aS218L mice displayed multiple-wave events, seemingly in line with the more severe clinical phenotype associated with the S218L mutation. Spontaneous CSDs were associated with body stretching, one-directional slow head turning, and rotating movement of the body. Spontaneous CSD events were compared with those induced in a controlled manner using minimally invasive optogenetics. Also in the optogenetic experiments single-wave CSDs were observed in Cacna1aR192Q and Cacna1aS218L mice (whereas the latter also showed multiple-wave events) with movements similar to those observed with spontaneous events. Compared to wildtype mice, FHM1 mutant mice exhibited a reduced threshold and an increased propagation speed for optogenetically induced CSD with a more profound CSD-associated dysfunction, as indicated by a prolonged suppression of transcallosal evoked potentials and a reduction of unilateral forepaw grip performance. When induced during sleep, the optogenetic CSD threshold was particularly lowered, which may explain why spontaneous CSD events predominantly occurred during sleep. In conclusion, our data show that key neurophysiological and behavioural features of optogenetically induced CSDs mimic those of rare spontaneous events in FHM1 R192Q and S218L mutant mice with differences in severity in line with FHM1 clinical phenotypes seen with these mutations.

Authors 6

1. Inge C. M. Loonen Aachen Department of Human Genetics

   Leiden University Medical Center

   Affiliation as printed

   Department of Human Genetics, Leiden University Medical Center, Leiden 2333 RC, the Netherlands

2. Rob A. Voskuyl Aachen Department of Human Genetics

   Leiden University Medical Center

   Affiliation as printed

   Department of Human Genetics, Leiden University Medical Center, Leiden 2333 RC, the Netherlands

3. Maarten Schenke Aachen Department of Human Genetics

   Leiden University Medical Center

   Affiliation as printed

   Department of Human Genetics, Leiden University Medical Center, Leiden 2333 RC, the Netherlands

4. Sandra H. van Heiningen Aachen Department of Human Genetics

   Leiden University Medical Center

   Affiliation as printed

   Department of Human Genetics, Leiden University Medical Center, Leiden 2333 RC, the Netherlands

5. Arn M. J. M. van den Maagdenberg Aachen Department of Human Genetics Department of Neurology, Leiden University Medical Center (LUMC)

   Leiden University · Leiden University Medical Center

   Affiliation as printed

   Department of Human Genetics, Leiden University Medical Center, Leiden 2333 RC, the Netherlands; Department of Neurology, Leiden University Medical Center, Leiden 2333 RC, the Netherlands

   Department of Human Genetics, Leiden University Medical Center, Leiden 2333 RC, the Netherlands

   Department of Neurology, Leiden University Medical Center, Leiden 2333 RC, the Netherlands

6. Else A. Tolner corresponding Aachen Department of Human Genetics Department of Neurology, Leiden University Medical Center (LUMC)

   Leiden University · Leiden University Medical Center

   Affiliation as printed

   Department of Human Genetics, Leiden University Medical Center, Leiden 2333 RC, the Netherlands; Department of Neurology, Leiden University Medical Center, Leiden 2333 RC, the Netherlands. Electronic address: E.A.Tolner@lumc.nl

   Department of Human Genetics, Leiden University Medical Center, Leiden 2333 RC, the Netherlands

   Department of Neurology, Leiden University Medical Center, Leiden 2333 RC, the Netherlands