High cortical spreading depression susceptibility and migraine-associated symptoms in Ca(v)2.1 S218L mice.
OBJECTIVE
The CACNA1A gene encodes the pore-forming subunit of neuronal Ca(V)2.1 Ca2+ 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.


CONCLUSIONS
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.
van den Maagdenberg
Arn M J M
AM
Department of Human Genetics, Leiden University Medical Centre, Leiden, The Netherlands. maagdenberg@lumc.nl
Pizzorusso
Tommaso
T
Kaja
Simon
S
Terpolilli
Nicole
N
Shapovalova
Maryna
M
Hoebeek
Freek E
FE
Barrett
Curtis F
CF
Gherardini
Lisa
L
van de Ven
Rob C G
RC
Todorov
Boyan
B
Broos
Ludo A M
LA
Tottene
Angelita
A
Gao
Zhenyu
Z
Fodor
Mariann
M
De Zeeuw
Chris I
CI
Frants
Rune R
RR
Plesnila
Nikolaus
N
Plomp
Jaap J
JJ
Pietrobon
Daniela
D
Ferrari
Michel D
MD
D000818:Animals; D001921:Brain / Q000503:physiopathology; D020864:Calcium Channels, N-Type; D020865:Calcium Channels, P-Type / Q000235:genetics* / Q000378:metabolism*; D020907:Calcium Channels, Q-Type / Q000235:genetics* / Q000378:metabolism*; D013181:Cortical Spreading Depression / Q000235:genetics* / Q000502:physiology*; D004195:Disease Models, Animal; D005260:Female; D020022:Genetic Predisposition to Disease; D008297:Male; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008881:Migraine Disorders / Q000235:genetics* / Q000503:physiopathology*; D020125:Mutation, Missense; D009469:Neuromuscular Junction / Q000503:physiopathology; D009474:Neurons / Q000502:physiology; D018377:Neurotransmitter Agents / Q000378:metabolism; D013577:Syndrome
D020864:Calcium Channels, N-Type; D020865:Calcium Channels, P-Type; D020907:Calcium Channels, Q-Type; D018377:Neurotransmitter Agents