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We used transgenic knock-in (KI) mice harboring the human pathogenic FHM1 mutation S218L to study presynaptic Ca<jats:sup>2+<\/jats:sup>currents, EPSCs, and<jats:italic>in vivo<\/jats:italic>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<jats:italic>I\u2013V<\/jats:italic>curve to more negative potentials, leading to an increase in basal [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub>, increased levels of spontaneous transmitter release, faster recovery from synaptic depression, and enhanced synaptic strength despite smaller action-potential-elicited Ca<jats:sup>2+<\/jats:sup>currents. The gain-of-function of transmitter release of the S218L mutant was reproduced<jats:italic>in vivo<\/jats:italic>, 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.<\/jats:p>","DOI":"10.1523\/jneurosci.2526-13.2014","type":"journal-article","created":{"date-parts":[[2014,5,21]],"date-time":"2014-05-21T17:05:00Z","timestamp":1400691900000},"page":"7047-7058","source":"Crossref","is-referenced-by-count":51,"title":["Synaptic Gain-of-Function Effects of Mutant Ca<sub>v<\/sub>2.1 Channels in a Mouse Model of Familial Hemiplegic Migraine Are Due to Increased Basal [Ca<sup>2+<\/sup>]<sub>i<\/sub>"],"prefix":"10.1523","volume":"34","author":[{"given":"Mariano N.","family":"Di Guilmi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiantian","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlota Gonzalez","family":"Inchauspe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian D.","family":"Forsythe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michel D.","family":"Ferrari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arn M.J.M.","family":"van den Maagdenberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. 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