Abnormal cortical synaptic transmission in CaV2.1 knockin mice with the S218L missense mutation which causes a severe familial hemiplegic migraine syndrome in humans

Frontiers in Cellular Neuroscience
Dania VecchiaD Pietrobon

Abstract

Familial hemiplegic migraine type 1 (FHM1) is caused by gain-of-function mutations in CaV2.1 (P/Q-type) Ca(2+) channels. Knockin (KI) mice carrying the FHM1 R192Q missense mutation show enhanced cortical excitatory synaptic transmission at pyramidal cell synapses but unaltered cortical inhibitory neurotransmission at fast-spiking interneuron synapses. Enhanced cortical glutamate release was shown to cause the facilitation of cortical spreading depression (CSD) in R192Q KI mice. It, however, remains unknown how other FHM1 mutations affect cortical synaptic transmission. Here, we studied neurotransmission in cortical neurons in microculture from KI mice carrying the S218L mutation, which causes a severe FHM syndrome in humans and an allele-dosage dependent facilitation of experimental CSD in KI mice, which is larger than that caused by the R192Q mutation. We show gain-of-function of excitatory neurotransmission, due to increased action-potential evoked Ca(2+) influx and increased probability of glutamate release at pyramidal cell synapses, but unaltered inhibitory neurotransmission at multipolar interneuron synapses in S218L KI mice. In contrast with the larger gain-of-function of neuronal CaV2.1 current in homozygous than hetero...Continue Reading

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Citations

Nov 7, 2015·Nature Reviews. Drug Discovery·Gerald W Zamponi
Jul 18, 2016·Journal of the Neurological Sciences·Claudia F GaspariniLyn R Griffiths
May 8, 2016·Cephalalgia : an International Journal of Headache·Shih-Pin ChenKatharina Eikermann-Haerter
Nov 23, 2018·Channels·Alexandra PinggeraJörg Striessnig
Sep 18, 2017·PM & R : the Journal of Injury, Function, and Rehabilitation·Manisha R ChandEvan Peck
Mar 30, 2019·Cephalalgia : an International Journal of Headache·Else A TolnerKatharina Eikermann-Haerter
Jun 30, 2016·EMBO Molecular Medicine·Clizia CapuaniDaniela Pietrobon
Mar 20, 2020·Cephalalgia : an International Journal of Headache·Matthijs Jl PerenboomElse A Tolner
May 17, 2019·Current Neuropharmacology·Anisa Dehghani, Hulya Karatas
Feb 23, 2017·Proceedings of the National Academy of Sciences of the United States of America·Stuart M CainTerrance P Snutch
Jan 17, 2019·Brain : a Journal of Neurology·Inge C M LoonenElse A Tolner
Mar 3, 2020·Frontiers in Molecular Neuroscience·Sidharth TyagiRoger A Bannister
Mar 13, 2020·Nature Reviews. Neuroscience·Annette C Dolphin, Amy Lee
Jul 14, 2019·The Journal of Headache and Pain·Daniela Pietrobon, K C Brennan
Jul 28, 2021·Nature Reviews. Neurology·Prisca R BauerJosemir W Sander

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Methods Mentioned

BETA
transgenic

Software Mentioned

pClamp
Clampfit

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