Gain of function in FHM-1 Cav2.1 knock-in mice is related to the shape of the action potential

Autores
González Inchauspe, Carlota María Fabiola; Urbano Suarez, Francisco Jose; Di Guilmi, Mariano Nicolás; Forsythe, Ian D.; Ferrari, Michel D.; Maagdenberg, Arn M. J. M. van den; Uchitel, Osvaldo Daniel
Año de publicación
2010
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Familial hemiplegic migraine type-1 FHM-1 is caused by missense mutations in the CACNA1A gene that encodes the α1A pore-forming subunit of CaV2.1 Ca2+ channels. We used knock-in (KI) transgenic mice harboring the pathogenic FHM-1 mutation R192Q to study neurotransmission at the calyx of Held synapse and cortical layer 2/3 pyramidal cells (PCs). Using whole cell patch-clamp recordings in brain stem slices, we confirmed that KI CaV2.1 Ca2+ channels activated at more hyperpolarizing potentials. However, calyceal presynaptic calcium currents (IpCa) evoked by presynaptic action potentials (APs) were similar in amplitude, kinetic parameters, and neurotransmitter release. CaV2.1 Ca2+ channels in cortical layer 2/3 PCs from KI mice also showed a negative shift in their activation voltage. PCs had APs with longer durations and smaller amplitudes than the calyx of Held. AP-evoked Ca2+ currents (I Ca) from PCs were larger in KI compared with wild-type (WT) mice. In contrast, when ICa was evoked in PCs by calyx of Held AP waveforms, we observed no amplitude differences between WT and KI mice. In the same way, Ca2+ currents evoked at the presynaptic terminals (IpCa)of the calyx of Held by the AP waveforms of the PCs had larger amplitudes in R192Q KI mice that in WT. These results suggest that longer time courses of pyramidal APs were a key factor for the expression of a synaptic gain of function in the KI mice. In addition, our results indicate that consequences of FHM-1 mutations might vary according to the shape of APs in charge of triggering synaptic transmission (neurons in the calyx of Held vs. excitatory/inhibitory neurons in the cortex), adding to the complexity of the pathophysiology of migraine.
Fil: González Inchauspe, Carlota María Fabiola. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina
Fil: Urbano Suarez, Francisco Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina
Fil: Di Guilmi, Mariano Nicolás. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina
Fil: Forsythe, Ian D.. University of Leicester; Reino Unido
Fil: Ferrari, Michel D.. Leiden University; Países Bajos
Fil: Maagdenberg, Arn M. J. M. van den. Leiden University; Países Bajos
Fil: Uchitel, Osvaldo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina
Materia
Calcium Channels
Calyx of herld
Synapsis
Migrania
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/100022

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network_name_str CONICET Digital (CONICET)
spelling Gain of function in FHM-1 Cav2.1 knock-in mice is related to the shape of the action potentialGonzález Inchauspe, Carlota María FabiolaUrbano Suarez, Francisco JoseDi Guilmi, Mariano NicolásForsythe, Ian D.Ferrari, Michel D.Maagdenberg, Arn M. J. M. van denUchitel, Osvaldo DanielCalcium ChannelsCalyx of herldSynapsisMigraniahttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Familial hemiplegic migraine type-1 FHM-1 is caused by missense mutations in the CACNA1A gene that encodes the α1A pore-forming subunit of CaV2.1 Ca2+ channels. We used knock-in (KI) transgenic mice harboring the pathogenic FHM-1 mutation R192Q to study neurotransmission at the calyx of Held synapse and cortical layer 2/3 pyramidal cells (PCs). Using whole cell patch-clamp recordings in brain stem slices, we confirmed that KI CaV2.1 Ca2+ channels activated at more hyperpolarizing potentials. However, calyceal presynaptic calcium currents (IpCa) evoked by presynaptic action potentials (APs) were similar in amplitude, kinetic parameters, and neurotransmitter release. CaV2.1 Ca2+ channels in cortical layer 2/3 PCs from KI mice also showed a negative shift in their activation voltage. PCs had APs with longer durations and smaller amplitudes than the calyx of Held. AP-evoked Ca2+ currents (I Ca) from PCs were larger in KI compared with wild-type (WT) mice. In contrast, when ICa was evoked in PCs by calyx of Held AP waveforms, we observed no amplitude differences between WT and KI mice. In the same way, Ca2+ currents evoked at the presynaptic terminals (IpCa)of the calyx of Held by the AP waveforms of the PCs had larger amplitudes in R192Q KI mice that in WT. These results suggest that longer time courses of pyramidal APs were a key factor for the expression of a synaptic gain of function in the KI mice. In addition, our results indicate that consequences of FHM-1 mutations might vary according to the shape of APs in charge of triggering synaptic transmission (neurons in the calyx of Held vs. excitatory/inhibitory neurons in the cortex), adding to the complexity of the pathophysiology of migraine.Fil: González Inchauspe, Carlota María Fabiola. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; ArgentinaFil: Urbano Suarez, Francisco Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; ArgentinaFil: Di Guilmi, Mariano Nicolás. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; ArgentinaFil: Forsythe, Ian D.. University of Leicester; Reino UnidoFil: Ferrari, Michel D.. Leiden University; Países BajosFil: Maagdenberg, Arn M. J. M. van den. Leiden University; Países BajosFil: Uchitel, Osvaldo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; ArgentinaAmerican Physiological Society2010-07info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/100022González Inchauspe, Carlota María Fabiola; Urbano Suarez, Francisco Jose; Di Guilmi, Mariano Nicolás; Forsythe, Ian D.; Ferrari, Michel D.; et al.; Gain of function in FHM-1 Cav2.1 knock-in mice is related to the shape of the action potential; American Physiological Society; Journal of Neurophysiology; 104; 1; 7-2010; 291-2990022-3077CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1152/jn.00034.2010info:eu-repo/semantics/altIdentifier/url/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2904224/info:eu-repo/semantics/altIdentifier/url/https://journals.physiology.org/doi/full/10.1152/jn.00034.2010info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:49:40Zoai:ri.conicet.gov.ar:11336/100022instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 09:49:41.145CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Gain of function in FHM-1 Cav2.1 knock-in mice is related to the shape of the action potential
title Gain of function in FHM-1 Cav2.1 knock-in mice is related to the shape of the action potential
spellingShingle Gain of function in FHM-1 Cav2.1 knock-in mice is related to the shape of the action potential
González Inchauspe, Carlota María Fabiola
Calcium Channels
Calyx of herld
Synapsis
Migrania
title_short Gain of function in FHM-1 Cav2.1 knock-in mice is related to the shape of the action potential
title_full Gain of function in FHM-1 Cav2.1 knock-in mice is related to the shape of the action potential
title_fullStr Gain of function in FHM-1 Cav2.1 knock-in mice is related to the shape of the action potential
title_full_unstemmed Gain of function in FHM-1 Cav2.1 knock-in mice is related to the shape of the action potential
title_sort Gain of function in FHM-1 Cav2.1 knock-in mice is related to the shape of the action potential
dc.creator.none.fl_str_mv González Inchauspe, Carlota María Fabiola
Urbano Suarez, Francisco Jose
Di Guilmi, Mariano Nicolás
Forsythe, Ian D.
Ferrari, Michel D.
Maagdenberg, Arn M. J. M. van den
Uchitel, Osvaldo Daniel
author González Inchauspe, Carlota María Fabiola
author_facet González Inchauspe, Carlota María Fabiola
Urbano Suarez, Francisco Jose
Di Guilmi, Mariano Nicolás
Forsythe, Ian D.
Ferrari, Michel D.
Maagdenberg, Arn M. J. M. van den
Uchitel, Osvaldo Daniel
author_role author
author2 Urbano Suarez, Francisco Jose
Di Guilmi, Mariano Nicolás
Forsythe, Ian D.
Ferrari, Michel D.
Maagdenberg, Arn M. J. M. van den
Uchitel, Osvaldo Daniel
author2_role author
author
author
author
author
author
dc.subject.none.fl_str_mv Calcium Channels
Calyx of herld
Synapsis
Migrania
topic Calcium Channels
Calyx of herld
Synapsis
Migrania
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Familial hemiplegic migraine type-1 FHM-1 is caused by missense mutations in the CACNA1A gene that encodes the α1A pore-forming subunit of CaV2.1 Ca2+ channels. We used knock-in (KI) transgenic mice harboring the pathogenic FHM-1 mutation R192Q to study neurotransmission at the calyx of Held synapse and cortical layer 2/3 pyramidal cells (PCs). Using whole cell patch-clamp recordings in brain stem slices, we confirmed that KI CaV2.1 Ca2+ channels activated at more hyperpolarizing potentials. However, calyceal presynaptic calcium currents (IpCa) evoked by presynaptic action potentials (APs) were similar in amplitude, kinetic parameters, and neurotransmitter release. CaV2.1 Ca2+ channels in cortical layer 2/3 PCs from KI mice also showed a negative shift in their activation voltage. PCs had APs with longer durations and smaller amplitudes than the calyx of Held. AP-evoked Ca2+ currents (I Ca) from PCs were larger in KI compared with wild-type (WT) mice. In contrast, when ICa was evoked in PCs by calyx of Held AP waveforms, we observed no amplitude differences between WT and KI mice. In the same way, Ca2+ currents evoked at the presynaptic terminals (IpCa)of the calyx of Held by the AP waveforms of the PCs had larger amplitudes in R192Q KI mice that in WT. These results suggest that longer time courses of pyramidal APs were a key factor for the expression of a synaptic gain of function in the KI mice. In addition, our results indicate that consequences of FHM-1 mutations might vary according to the shape of APs in charge of triggering synaptic transmission (neurons in the calyx of Held vs. excitatory/inhibitory neurons in the cortex), adding to the complexity of the pathophysiology of migraine.
Fil: González Inchauspe, Carlota María Fabiola. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina
Fil: Urbano Suarez, Francisco Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina
Fil: Di Guilmi, Mariano Nicolás. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina
Fil: Forsythe, Ian D.. University of Leicester; Reino Unido
Fil: Ferrari, Michel D.. Leiden University; Países Bajos
Fil: Maagdenberg, Arn M. J. M. van den. Leiden University; Países Bajos
Fil: Uchitel, Osvaldo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina
description Familial hemiplegic migraine type-1 FHM-1 is caused by missense mutations in the CACNA1A gene that encodes the α1A pore-forming subunit of CaV2.1 Ca2+ channels. We used knock-in (KI) transgenic mice harboring the pathogenic FHM-1 mutation R192Q to study neurotransmission at the calyx of Held synapse and cortical layer 2/3 pyramidal cells (PCs). Using whole cell patch-clamp recordings in brain stem slices, we confirmed that KI CaV2.1 Ca2+ channels activated at more hyperpolarizing potentials. However, calyceal presynaptic calcium currents (IpCa) evoked by presynaptic action potentials (APs) were similar in amplitude, kinetic parameters, and neurotransmitter release. CaV2.1 Ca2+ channels in cortical layer 2/3 PCs from KI mice also showed a negative shift in their activation voltage. PCs had APs with longer durations and smaller amplitudes than the calyx of Held. AP-evoked Ca2+ currents (I Ca) from PCs were larger in KI compared with wild-type (WT) mice. In contrast, when ICa was evoked in PCs by calyx of Held AP waveforms, we observed no amplitude differences between WT and KI mice. In the same way, Ca2+ currents evoked at the presynaptic terminals (IpCa)of the calyx of Held by the AP waveforms of the PCs had larger amplitudes in R192Q KI mice that in WT. These results suggest that longer time courses of pyramidal APs were a key factor for the expression of a synaptic gain of function in the KI mice. In addition, our results indicate that consequences of FHM-1 mutations might vary according to the shape of APs in charge of triggering synaptic transmission (neurons in the calyx of Held vs. excitatory/inhibitory neurons in the cortex), adding to the complexity of the pathophysiology of migraine.
publishDate 2010
dc.date.none.fl_str_mv 2010-07
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/100022
González Inchauspe, Carlota María Fabiola; Urbano Suarez, Francisco Jose; Di Guilmi, Mariano Nicolás; Forsythe, Ian D.; Ferrari, Michel D.; et al.; Gain of function in FHM-1 Cav2.1 knock-in mice is related to the shape of the action potential; American Physiological Society; Journal of Neurophysiology; 104; 1; 7-2010; 291-299
0022-3077
CONICET Digital
CONICET
url http://hdl.handle.net/11336/100022
identifier_str_mv González Inchauspe, Carlota María Fabiola; Urbano Suarez, Francisco Jose; Di Guilmi, Mariano Nicolás; Forsythe, Ian D.; Ferrari, Michel D.; et al.; Gain of function in FHM-1 Cav2.1 knock-in mice is related to the shape of the action potential; American Physiological Society; Journal of Neurophysiology; 104; 1; 7-2010; 291-299
0022-3077
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1152/jn.00034.2010
info:eu-repo/semantics/altIdentifier/url/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2904224/
info:eu-repo/semantics/altIdentifier/url/https://journals.physiology.org/doi/full/10.1152/jn.00034.2010
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv American Physiological Society
publisher.none.fl_str_mv American Physiological Society
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
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reponame_str CONICET Digital (CONICET)
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instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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