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Abstract:

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.

Registro:

Documento: Artículo
Título:Familial hemiplegic migraine type-1 mutated cav2.1 calcium channels alter inhibitory and excitatory synaptic transmission in the lateral superior olive of mice
Autor:Inchauspe, C.G.; Pilati, N.; Di Guilmi, M.N.; Urbano, F.J.; Ferrari, M.D.; van den Maagdenberg, A.M.J.M.; Forsythe, I.D.; Uchitel, O.D.
Filiación:Instituto de Fisiología Biología molecular y Neurociencias, CONICET Departamento de Fisiología Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales Universidad de Buenos Aires, Argentina
Dept Cell Physiology and Pharmacology, University of LeicesterLE1 9HN, United Kingdom
Department of Neurology, Leiden University Medical Centre, P.O. Box 9600, RC Leiden, 2300, Netherlands
Department of Human Genetics, Leiden University Medical Centre, P.O. Box 9600, RC Leiden, 2300, Netherlands
Autifony S.r.l. Via Fleming 4, Verona (VR), 37135, Italy
Palabras clave: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
Año:2015
Volumen:319
Página de inicio:56
Página de fin:68
DOI: http://dx.doi.org/10.1016/j.heares.2014.11.006
Título revista:Hearing Research
Título revista abreviado:Hear. Res.
ISSN:03785955
CODEN:HERED
CAS:arginine, 1119-34-2, 15595-35-4, 7004-12-8, 74-79-3; glutamine, 56-85-9, 6899-04-3; glycine, 56-40-6, 6000-43-7, 6000-44-8; Calcium Channels, N-Type; Codon; Glutamine; Glycine; Neurotransmitter Agents; voltage-dependent calcium channel (P-Q type)
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_03785955_v319_n_p56_Inchauspe

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Citas:

---------- APA ----------
Inchauspe, C.G., Pilati, N., Di Guilmi, M.N., Urbano, F.J., Ferrari, M.D., van den Maagdenberg, A.M.J.M., Forsythe, I.D.,..., Uchitel, O.D. (2015) . Familial hemiplegic migraine type-1 mutated cav2.1 calcium channels alter inhibitory and excitatory synaptic transmission in the lateral superior olive of mice. Hearing Research, 319, 56-68.
http://dx.doi.org/10.1016/j.heares.2014.11.006
---------- CHICAGO ----------
Inchauspe, C.G., Pilati, N., Di Guilmi, M.N., Urbano, F.J., Ferrari, M.D., van den Maagdenberg, A.M.J.M., et al. "Familial hemiplegic migraine type-1 mutated cav2.1 calcium channels alter inhibitory and excitatory synaptic transmission in the lateral superior olive of mice" . Hearing Research 319 (2015) : 56-68.
http://dx.doi.org/10.1016/j.heares.2014.11.006
---------- MLA ----------
Inchauspe, C.G., Pilati, N., Di Guilmi, M.N., Urbano, F.J., Ferrari, M.D., van den Maagdenberg, A.M.J.M., et al. "Familial hemiplegic migraine type-1 mutated cav2.1 calcium channels alter inhibitory and excitatory synaptic transmission in the lateral superior olive of mice" . Hearing Research, vol. 319, 2015, pp. 56-68.
http://dx.doi.org/10.1016/j.heares.2014.11.006
---------- VANCOUVER ----------
Inchauspe, C.G., Pilati, N., Di Guilmi, M.N., Urbano, F.J., Ferrari, M.D., van den Maagdenberg, A.M.J.M., et al. Familial hemiplegic migraine type-1 mutated cav2.1 calcium channels alter inhibitory and excitatory synaptic transmission in the lateral superior olive of mice. Hear. Res. 2015;319:56-68.
http://dx.doi.org/10.1016/j.heares.2014.11.006