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High cortical spreading depression susceptibility and migraine‐associated symptoms in Ca v 2.1 S218L mice
Author(s) -
van den Maagdenberg Arn M. J. M.,
Pizzorusso Tommaso,
Kaja Simon,
Terpolilli Nicole,
Shapovalova Maryna,
Hoebeek Freek E.,
Barrett Curtis F.,
Gherardini Lisa,
van de Ven Rob C. G.,
Todorov Boyan,
Broos Ludo A. M.,
Tottene Angelita,
Gao Zhenyu,
Fodor Mariann,
De Zeeuw Chris I.,
Frants Rune R.,
Plesnila Nikolaus,
Plomp Jaap J.,
Pietrobon Daniela,
Ferrari Michel D.
Publication year - 2010
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.21815
Subject(s) - cortical spreading depression , familial hemiplegic migraine , neuroscience , ataxia , stimulus (psychology) , migraine , cerebral cortex , medicine , biology , psychology , migraine with aura , aura , psychotherapist
Objective The CACNA1A gene encodes the pore‐forming subunit of neuronal Ca V 2.1 Ca 2+ channels. In patients, the S218L CACNA1A mutation causes a dramatic hemiplegic migraine syndrome that is associated with ataxia, seizures, and severe, sometimes fatal, brain edema often triggered by only a mild head trauma. Methods We introduced the S218L mutation into the mouse Cacna1a gene and studied the mechanisms for the S218L syndrome by analyzing the phenotypic, molecular, and electrophysiological consequences. Results Cacna1a S218L mice faithfully mimic the associated clinical features of the human S218L syndrome. S218L neurons exhibit a gene dosage–dependent negative shift in voltage dependence of Ca V 2.1 channel activation, resulting in enhanced neurotransmitter release at the neuromuscular junction. Cacna1a S218L mice also display an exquisite sensitivity to cortical spreading depression (CSD), with a vastly reduced triggering threshold, an increased propagation velocity, and frequently multiple CSD events after a single stimulus. In contrast, mice bearing the R192Q CACNA1A mutation, which in humans causes a milder form of hemiplegic migraine, typically exhibit only a single CSD event after one triggering stimulus. Interpretation The particularly low CSD threshold and the strong tendency to respond with multiple CSD events make the S218L cortex highly vulnerable to weak stimuli and may provide a mechanistic basis for the dramatic phenotype seen in S218L mice and patients. Thus, the S218L mouse model may prove a valuable tool to further elucidate mechanisms underlying migraine, seizures, ataxia, and trauma‐triggered cerebral edema. ANN NEUROL 2010;67:85–98