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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

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journal contribution
posted on 24.09.2014, 15:40 by Mariano N. Di Guilmi, Tiantian Wang, Carlota Gonzalez Inchauspe, Ian D. Forsythe, Michel D. Ferrari, Arn M. J. M. van den Maagdenberg, J. Gerard Borst, Osvaldo D. Uchitel
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.

History

Citation

Journal of Neuroscience, 2014, 34 (21), pp. 7047-7058

Author affiliation

/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/School of Biological Sciences/Department of Cell Physiology and Pharmacology

Version

VoR (Version of Record)

Published in

Journal of Neuroscience

Publisher

Society for Neuroscience

issn

0270-6474

eissn

1529-2401

Copyright date

2014

Available date

21/11/2014

Publisher version

http://www.jneurosci.org/content/34/21/7047

Language

en