title: Severe and progressive neurotransmitter release aberrations in familial hemiplegic migraine type 1 Cacna1a S218L knock-in mice.
abstract: Familial hemiplegic migraine type 1 (FHM1) is caused by mutations in the CACNA1A gene, encoding neuronal presynaptic Ca(V)2.1 (P/Q-type) Ca(2+) channels. These channels mediate neurotransmitter release at many central synapses and at the neuromuscular junction (NMJ). Mutation S218L causes a severe neurological phenotype of FHM and, additionally, ataxia and susceptibility to seizures, delayed brain edema, and fatal coma after minor head trauma. Recently, we generated a Cacna1a S218L knock-in mutant mouse, displaying these features and reduced survival. A first electrophysiological study showed high susceptibility for cortical spreading depression, enhanced neuronal soma Ca(2+) influx, and at diaphragm NMJs, a considerable increase of neurotransmitter release. We here assessed the function of S218L knock-in NMJs at several muscle types in great detail. Pharmacological analyses using specific Ca(V) subtype-blocking toxins excluded compensatory contribution of non-Ca(V)2.1 channels. Endplate potentials were considerably broadened at many NMJs. High rate (40 Hz)-evoked acetylcholine release was slightly reduced; however, it was not associated with block of neurotransmission causing weakness, as assessed with grip strength measurements and in vitro muscle contraction experiments. The synaptopathy clearly progressed with age, including development of an increased acetylcholine release at low-rate nerve stimulation at physiological extracellular Ca(2+) concentration and further endplate potential broadening. Our results suggest enhanced Ca(2+) influx into motor nerve terminals through S218L-mutated presynaptic Ca(V)2.1 channels, likely because of the earlier reported negative shift of activation potential and reduced inactivation. Similar severe aberrations at central synapses of S218L mutant mice and humans may underlie or contribute to the drastic neurological phenotype.
authors.affiliation: Department of Neurology, Leiden Univ. Medical Ctr., Leiden, The Netherlands.
authors.forename: Simon
authors.initials: S
authors.lastname: Kaja
authors.forename: Rob C G
authors.initials: RC
authors.lastname: Van de Ven
authors.forename: Ludo A M
authors.initials: LA
authors.lastname: Broos
authors.forename: Rune R
authors.initials: RR
authors.lastname: Frants
authors.forename: Michel D
authors.initials: MD
authors.lastname: Ferrari
authors.forename: Arn M J M
authors.initials: AM
authors.lastname: Van den Maagdenberg
authors.forename: Jaap J
authors.initials: JJ
authors.lastname: Plomp
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D020864:Calcium Channels, N-Type; D020865:Calcium Channels, P-Type / Q000096:biosynthesis / Q000235:genetics*; D020907:Calcium Channels, Q-Type / Q000096:biosynthesis / Q000235:genetics*; D018450:Disease Progression; D005260:Female; D055879:Gene Knock-In Techniques; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D020325:Migraine with Aura / Q000235:genetics* / Q000378:metabolism; D055369:Miniature Postsynaptic Potentials / Q000502:physiology; D009469:Neuromuscular Junction / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000378:metabolism; D012720:Severity of Illness Index; D009435:Synaptic Transmission / Q000235:genetics
chemical_list: D000109:Acetylcholine; D020864:Calcium Channels, N-Type; D020865:Calcium Channels, P-Type; D020907:Calcium Channels, Q-Type; D018377:Neurotransmitter Agents