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...
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2014
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| Acceso en línea: | https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_02706474_v34_n21_p7047_DiGuilmi http://hdl.handle.net/20.500.12110/paper_02706474_v34_n21_p7047_DiGuilmi |
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paper:paper_02706474_v34_n21_p7047_DiGuilmi2025-07-30T18:02:49Z 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 Calyx of Held FHM-1 In vivo P/Q calcium channels Synaptic transmission unclassified drug voltage gated calcium channel voltage gated calcium channel 2.1 action potential adult animal experiment animal model animal tissue article auditory stimulation calcium current calyx of held controlled study electrophysiology excitatory postsynaptic potential familial hemiplegic migraine gain of function mutation mouse neurotransmitter release nonhuman presynaptic membrane priority journal synapse synaptic transmission whole cell patch clamp calyx of Held FHM-1 in vivo P/Q calcium channels synaptic transmission Agatoxins Animals Brain Stem Calcium Calcium Channels, N-Type Disease Models, Animal Humans Mice Mice, Inbred C57BL Mice, Transgenic Migraine with Aura Mutation Neurotoxins Sodium Channel Blockers Synapses Tetrodotoxin Time Factors 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. © 2014 the authors. 2014 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_02706474_v34_n21_p7047_DiGuilmi http://hdl.handle.net/20.500.12110/paper_02706474_v34_n21_p7047_DiGuilmi |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
Calyx of Held FHM-1 In vivo P/Q calcium channels Synaptic transmission unclassified drug voltage gated calcium channel voltage gated calcium channel 2.1 action potential adult animal experiment animal model animal tissue article auditory stimulation calcium current calyx of held controlled study electrophysiology excitatory postsynaptic potential familial hemiplegic migraine gain of function mutation mouse neurotransmitter release nonhuman presynaptic membrane priority journal synapse synaptic transmission whole cell patch clamp calyx of Held FHM-1 in vivo P/Q calcium channels synaptic transmission Agatoxins Animals Brain Stem Calcium Calcium Channels, N-Type Disease Models, Animal Humans Mice Mice, Inbred C57BL Mice, Transgenic Migraine with Aura Mutation Neurotoxins Sodium Channel Blockers Synapses Tetrodotoxin Time Factors |
| spellingShingle |
Calyx of Held FHM-1 In vivo P/Q calcium channels Synaptic transmission unclassified drug voltage gated calcium channel voltage gated calcium channel 2.1 action potential adult animal experiment animal model animal tissue article auditory stimulation calcium current calyx of held controlled study electrophysiology excitatory postsynaptic potential familial hemiplegic migraine gain of function mutation mouse neurotransmitter release nonhuman presynaptic membrane priority journal synapse synaptic transmission whole cell patch clamp calyx of Held FHM-1 in vivo P/Q calcium channels synaptic transmission Agatoxins Animals Brain Stem Calcium Calcium Channels, N-Type Disease Models, Animal Humans Mice Mice, Inbred C57BL Mice, Transgenic Migraine with Aura Mutation Neurotoxins Sodium Channel Blockers Synapses Tetrodotoxin Time Factors 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 |
| topic_facet |
Calyx of Held FHM-1 In vivo P/Q calcium channels Synaptic transmission unclassified drug voltage gated calcium channel voltage gated calcium channel 2.1 action potential adult animal experiment animal model animal tissue article auditory stimulation calcium current calyx of held controlled study electrophysiology excitatory postsynaptic potential familial hemiplegic migraine gain of function mutation mouse neurotransmitter release nonhuman presynaptic membrane priority journal synapse synaptic transmission whole cell patch clamp calyx of Held FHM-1 in vivo P/Q calcium channels synaptic transmission Agatoxins Animals Brain Stem Calcium Calcium Channels, N-Type Disease Models, Animal Humans Mice Mice, Inbred C57BL Mice, Transgenic Migraine with Aura Mutation Neurotoxins Sodium Channel Blockers Synapses Tetrodotoxin Time Factors |
| description |
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. © 2014 the authors. |
| title |
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 |
| title_short |
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 |
| title_full |
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 |
| title_fullStr |
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 |
| title_full_unstemmed |
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 |
| title_sort |
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 |
| publishDate |
2014 |
| url |
https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_02706474_v34_n21_p7047_DiGuilmi http://hdl.handle.net/20.500.12110/paper_02706474_v34_n21_p7047_DiGuilmi |
| _version_ |
1840324570151649280 |