Severe and progressive neurotransmitter release aberrations in familial hemiplegic migraine type 1 Cacna1a S218L knock-in mice

Journal of Neurophysiology
S KajaJaap J Plomp

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 measuremen...Continue Reading

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Citations

Oct 12, 2012·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Achim KlugMatthew A Xu-Friedman
Nov 15, 2011·Journal of Physiology, Paris·Osvaldo D UchitelMariano N Di Guilmi
Mar 21, 2012·Muscle & Nerve·Louis S StodieckVirginia L Ferguson
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Mar 1, 2014·Biophysics Reviews·Osvaldo D UchitelMariano N Di Guilmi
May 15, 2021·Orphanet Journal of Rare Diseases·Miriam KessiFei Yin

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