Synaptic gain-of-function effects of mutant Cav2.1 channels in a mouse model of familial hemiplegic migraine are due to increased basal [Ca2+]i.
Specific missense mutations in the CACNA1A gene, which encodes a subunit of voltage-gated CaV2.1 channels, are associated with familial hemiplegic migraine type 1 (FHM1), a rare monogenic subtype of common migraine with aura. We used transgenic knock-in (KI) mice harboring the human pathogenic FHM1 mutation S218L to study presynaptic Ca(2+) currents, EPSCs, and in vivo activity at the calyx of Held synapse. Whole-cell patch-clamp recordings of presynaptic terminals from S218L KI mice showed a strong shift of the calcium current I-V curve to more negative potentials, leading to an increase in basal [Ca(2+)]i, increased levels of spontaneous transmitter release, faster recovery from synaptic depression, and enhanced synaptic strength despite smaller action-potential-elicited Ca(2+) currents. The gain-of-function of transmitter release of the S218L mutant was reproduced in vivo, including evidence for an increased release probability, demonstrating its relevance for glutamatergic transmission. This synaptic phenotype may explain the misbalance between excitation and inhibition in neuronal circuits resulting in a persistent hyperexcitability state and other migraine-relevant mechanisms such as an increased susceptibility to cortical spreading depression.
Institute of Physiology, Molecular Biology and Neuroscience (IFIBYNE, UBA-CONICET), Department of Physiology, Molecular, and Cell Biology, University of Buenos Aires, Buenos Aires C1428EHA, Argentina.
Mariano N
MN
Di Guilmi
Department of Neuroscience, Erasmus MC, University Medical Center, Rotterdam NL-3000 CA, The Netherlands.
Tiantian
T
Wang
Institute of Physiology, Molecular Biology and Neuroscience (IFIBYNE, UBA-CONICET), Department of Physiology, Molecular, and Cell Biology, University of Buenos Aires, Buenos Aires C1428EHA, Argentina.
Carlota Gonzalez
CG
Inchauspe
Neurotoxicity at the Synaptic Interface, Medical Research Council Toxicology Unit, University of Leicester, Leicester LE1 9HN, United Kingdom, and.
Ian D
ID
Forsythe
Department of Neurology and.
Michel D
MD
Ferrari
Department of Neurology and Department of Human Genetics, Leiden University Medical Center, Leiden 2300 RC, The Netherlands.
Arn M J M
AM
van den Maagdenberg
Department of Neuroscience, Erasmus MC, University Medical Center, Rotterdam NL-3000 CA, The Netherlands.
J Gerard G
JG
Borst
Institute of Physiology, Molecular Biology and Neuroscience (IFIBYNE, UBA-CONICET), Department of Physiology, Molecular, and Cell Biology, University of Buenos Aires, Buenos Aires C1428EHA, Argentina, ouchitel@gmail.com.
Osvaldo D
OD
Uchitel
D060848:Agatoxins / Q000494:pharmacology; D000818:Animals; D001933:Brain Stem / Q000166:cytology / Q000502:physiology*; D002118:Calcium / Q000378:metabolism*; D020864:Calcium Channels, N-Type / Q000235:genetics*; D004195:Disease Models, Animal; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020325:Migraine with Aura / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D009154:Mutation / Q000235:genetics*; D009498:Neurotoxins / Q000494:pharmacology; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013569:Synapses / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D013779:Tetrodotoxin / Q000494:pharmacology; D013997:Time Factors
D060848:Agatoxins; D002118:Calcium; D020864:Calcium Channels, N-Type; D009498:Neurotoxins; D026941:Sodium Channel Blockers; D013779:Tetrodotoxin
FHM-1; P/Q calcium channels; calyx of Held; in vivo; synaptic transmission