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Title: Synaptic gain-of-function effects of mutant Ca[subscript v]2.1 channels in a mouse model of familial hemiplegic migraine are due to increased basal [Ca[superscript 2+]]i
Authors: Di Guilmi, Mariano N.
Wang, Tiantian
Inchauspe, Carlota Gonzalez
Forsythe, Ian D.
Ferrari, Michel D.
van den Maagdenberg, Arn M. J. M.
Borst, J. Gerard
Uchitel, Osvaldo D.
First Published: 21-May-2014
Publisher: Society for Neuroscience
Citation: Journal of Neuroscience, 2014, 34 (21), pp. 7047-7058
Abstract: Specific missense mutations in the CACNA1A gene, which encodes a subunit of voltage-gated Ca[subscript V]2.1 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[superscript 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[superscript 2+]]i, increased levels of spontaneous transmitter release, faster recovery from synaptic depression, and enhanced synaptic strength despite smaller action-potential-elicited Ca[superscript 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.
DOI Link: 10.1523/JNEUROSCI.2526-13.2014
ISSN: 0270-6474
eISSN: 1529-2401
Version: Publisher Version
Status: Peer-reviewed
Type: Journal Article
Rights: Copyright © 2014, Society for Neuroscience. Deposited with reference to the publisher’s archiving policy available on the SHERPA/RoMEO website.
Appears in Collections:Published Articles, Dept. of Cell Physiology and Pharmacology

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