Familial hemiplegic migraine type-1 mutated cav2.1 calcium channels alter inhibitory and excitatory synaptic transmission in the lateral superior olive of mice

CaV2.1 Ca2+ channels play a key role in triggering neurotransmitter release and mediating synaptic transmission. 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) tr...

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Autores principales:	Di Guilmi, Mariano Nicolas, Uchitel, Osvaldo Daniel
Publicado:	2015
Materias:	arginine calcium channel calcium channel CaV2.1 glutamine unclassified drug agents interacting with transmitter, hormone or drug receptors calcium channel N type codon glycine voltage-dependent calcium channel (P-Q type) animal cell animal experiment Article auditory nervous system brain stem controlled study evoked response excitatory synaptic transmission familial hemiplegic migraine familial hemiplegic migraine type 1 inhibitory synaptic transmission lateral superior olive missense mutation mouse mutational analysis nerve cell nerve cell plasticity nerve excitability nerve stimulation nervous system parameters neurotransmission nonhuman pathophysiology postsynaptic potential protein function sensory nerve short term depression superior olivary nucleus synaptic transmission transgenic mouse animal cerebellar ataxia chemistry electrophysiology exon genetics metabolism migraine mutation probability Animals Brain Stem Calcium Channels, N-Type Cerebellar Ataxia Codon Electrophysiology Exons Glutamine Glycine Mice Mice, Transgenic Migraine Disorders Mutation Neuronal Plasticity Neurons Neurotransmitter Agents Probability Superior Olivary Complex Synaptic Transmission
Acceso en línea:	https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_03785955_v319_n_p56_Inchauspe http://hdl.handle.net/20.500.12110/paper_03785955_v319_n_p56_Inchauspe
Aporte de:	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) de Universidad de Buenos Aires

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spelling	paper:paper_03785955_v319_n_p56_Inchauspe2023-06-08T15:40:25Z Familial hemiplegic migraine type-1 mutated cav2.1 calcium channels alter inhibitory and excitatory synaptic transmission in the lateral superior olive of mice Di Guilmi, Mariano Nicolas Uchitel, Osvaldo Daniel arginine calcium channel calcium channel CaV2.1 glutamine unclassified drug agents interacting with transmitter, hormone or drug receptors calcium channel N type codon glutamine glycine voltage-dependent calcium channel (P-Q type) animal cell animal experiment Article auditory nervous system brain stem controlled study evoked response excitatory synaptic transmission familial hemiplegic migraine familial hemiplegic migraine type 1 inhibitory synaptic transmission lateral superior olive missense mutation mouse mutational analysis nerve cell nerve cell plasticity nerve excitability nerve stimulation nervous system parameters neurotransmission nonhuman pathophysiology postsynaptic potential protein function sensory nerve short term depression superior olivary nucleus synaptic transmission transgenic mouse animal cerebellar ataxia chemistry codon electrophysiology exon genetics metabolism migraine mutation probability superior olivary nucleus Animals Brain Stem Calcium Channels, N-Type Cerebellar Ataxia Codon Electrophysiology Exons Glutamine Glycine Mice Mice, Transgenic Migraine Disorders Mutation Neuronal Plasticity Neurons Neurotransmitter Agents Probability Superior Olivary Complex Synaptic Transmission CaV2.1 Ca2+ channels play a key role in triggering neurotransmitter release and mediating synaptic transmission. 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 harbouring the pathogenic FHM-1 mutation R192Q to study inhibitory and excitatory neurotransmission in the principle neurons of the lateral superior olive (LSO) in the auditory brainstem. We tested if the R192Q FHM-1 mutation differentially affects excitatory and inhibitory synaptic transmission, disturbing the normal balance between excitation and inhibition in this nucleus. Whole cell patch-clamp was used to measure neurotransmitter elicited excitatory (EPSCs) and inhibitory (IPSCs) postsynaptic currents in wild-type (WT) and R192Q KI mice. Our results showed that the FHM-1 mutation in CaV2.1 channels has multiple effects. Evoked EPSC amplitudes were smaller whereas evoked and miniature IPSC amplitudes were larger in R192Q KI compared to WT mice. In addition, in R192Q KI mice, the release probability was enhanced compared to WT, at both inhibitory (0.53±0.02 vs. 0.44±0.01, P=2.10-5, Student's t-test) and excitatory synapses (0.60±0.03 vs. 0.45±0.02, P=4 10-6, Student's t-test). Vesicle pool size was diminished in R192Q KI mice compared to WT mice (68±6 vs 91±7, P=0.008, inhibitory; 104±13 vs 335±30, P=10-6, excitatory, Student's t-test). R192Q KI mice present enhanced short-term plasticity. Repetitive stimulation of the afferent axons caused short-term depression (STD) of E/IPSCs that recovered significantly faster in R192Q KI mice compared to WT. This supports the hypothesis of a gain-of-function of the CaV2.1 channels in R192Q KI mice, which alters the balance of excitatory/inhibitory inputs and could also have implications in the altered cortical excitability responsible for FHM pathology. © 2014 Elsevier B.V. Fil:Di Guilmi, M.N. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Uchitel, O.D. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. 2015 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_03785955_v319_n_p56_Inchauspe http://hdl.handle.net/20.500.12110/paper_03785955_v319_n_p56_Inchauspe
institution	Universidad de Buenos Aires
institution_str	I-28
repository_str	R-134
collection	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA)
topic	arginine calcium channel calcium channel CaV2.1 glutamine unclassified drug agents interacting with transmitter, hormone or drug receptors calcium channel N type codon glutamine glycine voltage-dependent calcium channel (P-Q type) animal cell animal experiment Article auditory nervous system brain stem controlled study evoked response excitatory synaptic transmission familial hemiplegic migraine familial hemiplegic migraine type 1 inhibitory synaptic transmission lateral superior olive missense mutation mouse mutational analysis nerve cell nerve cell plasticity nerve excitability nerve stimulation nervous system parameters neurotransmission nonhuman pathophysiology postsynaptic potential protein function sensory nerve short term depression superior olivary nucleus synaptic transmission transgenic mouse animal cerebellar ataxia chemistry codon electrophysiology exon genetics metabolism migraine mutation probability superior olivary nucleus Animals Brain Stem Calcium Channels, N-Type Cerebellar Ataxia Codon Electrophysiology Exons Glutamine Glycine Mice Mice, Transgenic Migraine Disorders Mutation Neuronal Plasticity Neurons Neurotransmitter Agents Probability Superior Olivary Complex Synaptic Transmission
spellingShingle	arginine calcium channel calcium channel CaV2.1 glutamine unclassified drug agents interacting with transmitter, hormone or drug receptors calcium channel N type codon glutamine glycine voltage-dependent calcium channel (P-Q type) animal cell animal experiment Article auditory nervous system brain stem controlled study evoked response excitatory synaptic transmission familial hemiplegic migraine familial hemiplegic migraine type 1 inhibitory synaptic transmission lateral superior olive missense mutation mouse mutational analysis nerve cell nerve cell plasticity nerve excitability nerve stimulation nervous system parameters neurotransmission nonhuman pathophysiology postsynaptic potential protein function sensory nerve short term depression superior olivary nucleus synaptic transmission transgenic mouse animal cerebellar ataxia chemistry codon electrophysiology exon genetics metabolism migraine mutation probability superior olivary nucleus Animals Brain Stem Calcium Channels, N-Type Cerebellar Ataxia Codon Electrophysiology Exons Glutamine Glycine Mice Mice, Transgenic Migraine Disorders Mutation Neuronal Plasticity Neurons Neurotransmitter Agents Probability Superior Olivary Complex Synaptic Transmission Di Guilmi, Mariano Nicolas Uchitel, Osvaldo Daniel Familial hemiplegic migraine type-1 mutated cav2.1 calcium channels alter inhibitory and excitatory synaptic transmission in the lateral superior olive of mice
topic_facet	arginine calcium channel calcium channel CaV2.1 glutamine unclassified drug agents interacting with transmitter, hormone or drug receptors calcium channel N type codon glutamine glycine voltage-dependent calcium channel (P-Q type) animal cell animal experiment Article auditory nervous system brain stem controlled study evoked response excitatory synaptic transmission familial hemiplegic migraine familial hemiplegic migraine type 1 inhibitory synaptic transmission lateral superior olive missense mutation mouse mutational analysis nerve cell nerve cell plasticity nerve excitability nerve stimulation nervous system parameters neurotransmission nonhuman pathophysiology postsynaptic potential protein function sensory nerve short term depression superior olivary nucleus synaptic transmission transgenic mouse animal cerebellar ataxia chemistry codon electrophysiology exon genetics metabolism migraine mutation probability superior olivary nucleus Animals Brain Stem Calcium Channels, N-Type Cerebellar Ataxia Codon Electrophysiology Exons Glutamine Glycine Mice Mice, Transgenic Migraine Disorders Mutation Neuronal Plasticity Neurons Neurotransmitter Agents Probability Superior Olivary Complex Synaptic Transmission
description	CaV2.1 Ca2+ channels play a key role in triggering neurotransmitter release and mediating synaptic transmission. 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 harbouring the pathogenic FHM-1 mutation R192Q to study inhibitory and excitatory neurotransmission in the principle neurons of the lateral superior olive (LSO) in the auditory brainstem. We tested if the R192Q FHM-1 mutation differentially affects excitatory and inhibitory synaptic transmission, disturbing the normal balance between excitation and inhibition in this nucleus. Whole cell patch-clamp was used to measure neurotransmitter elicited excitatory (EPSCs) and inhibitory (IPSCs) postsynaptic currents in wild-type (WT) and R192Q KI mice. Our results showed that the FHM-1 mutation in CaV2.1 channels has multiple effects. Evoked EPSC amplitudes were smaller whereas evoked and miniature IPSC amplitudes were larger in R192Q KI compared to WT mice. In addition, in R192Q KI mice, the release probability was enhanced compared to WT, at both inhibitory (0.53±0.02 vs. 0.44±0.01, P=2.10-5, Student's t-test) and excitatory synapses (0.60±0.03 vs. 0.45±0.02, P=4 10-6, Student's t-test). Vesicle pool size was diminished in R192Q KI mice compared to WT mice (68±6 vs 91±7, P=0.008, inhibitory; 104±13 vs 335±30, P=10-6, excitatory, Student's t-test). R192Q KI mice present enhanced short-term plasticity. Repetitive stimulation of the afferent axons caused short-term depression (STD) of E/IPSCs that recovered significantly faster in R192Q KI mice compared to WT. This supports the hypothesis of a gain-of-function of the CaV2.1 channels in R192Q KI mice, which alters the balance of excitatory/inhibitory inputs and could also have implications in the altered cortical excitability responsible for FHM pathology. © 2014 Elsevier B.V.
author	Di Guilmi, Mariano Nicolas Uchitel, Osvaldo Daniel
author_facet	Di Guilmi, Mariano Nicolas Uchitel, Osvaldo Daniel
author_sort	Di Guilmi, Mariano Nicolas
title	Familial hemiplegic migraine type-1 mutated cav2.1 calcium channels alter inhibitory and excitatory synaptic transmission in the lateral superior olive of mice
title_short	Familial hemiplegic migraine type-1 mutated cav2.1 calcium channels alter inhibitory and excitatory synaptic transmission in the lateral superior olive of mice
title_full	Familial hemiplegic migraine type-1 mutated cav2.1 calcium channels alter inhibitory and excitatory synaptic transmission in the lateral superior olive of mice
title_fullStr	Familial hemiplegic migraine type-1 mutated cav2.1 calcium channels alter inhibitory and excitatory synaptic transmission in the lateral superior olive of mice
title_full_unstemmed	Familial hemiplegic migraine type-1 mutated cav2.1 calcium channels alter inhibitory and excitatory synaptic transmission in the lateral superior olive of mice
title_sort	familial hemiplegic migraine type-1 mutated cav2.1 calcium channels alter inhibitory and excitatory synaptic transmission in the lateral superior olive of mice
publishDate	2015
url	https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_03785955_v319_n_p56_Inchauspe http://hdl.handle.net/20.500.12110/paper_03785955_v319_n_p56_Inchauspe
work_keys_str_mv	AT diguilmimarianonicolas familialhemiplegicmigrainetype1mutatedcav21calciumchannelsalterinhibitoryandexcitatorysynaptictransmissioninthelateralsuperioroliveofmice AT uchitelosvaldodaniel familialhemiplegicmigrainetype1mutatedcav21calciumchannelsalterinhibitoryandexcitatorysynaptictransmissioninthelateralsuperioroliveofmice
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Familial hemiplegic migraine type-1 mutated cav2.1 calcium channels alter inhibitory and excitatory synaptic transmission in the lateral superior olive of mice

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