Inhibitory synaptic transmission is impaired at higher extracellular Ca2+ concentrations in Scn1a +/− mouse model of Dravet syndrome
Abstract Dravet syndrome (DS) is an intractable form of childhood epilepsy that occurs in infancy. More than 80% of all patients have a heterozygous abnormality in the SCN1A gene, which encodes a subunit of Na+ channels in the brain. However, the detailed pathogenesis of DS remains unclear. This stu...
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doaj-f6e6c8cce3c4492e8c1aea934931d3d82021-05-23T11:32:53ZengNature Publishing GroupScientific Reports2045-23222021-05-0111111110.1038/s41598-021-90224-4Inhibitory synaptic transmission is impaired at higher extracellular Ca2+ concentrations in Scn1a +/− mouse model of Dravet syndromeKouya Uchino0Hiroyuki Kawano1Yasuyoshi Tanaka2Yuna Adaniya3Ai Asahara4Masanobu Deshimaru5Kaori Kubota6Takuya Watanabe7Shutaro Katsurabayashi8Katsunori Iwasaki9Shinichi Hirose10Department of Neuropharmacology, Faculty of Pharmaceutical Sciences, Fukuoka UniversityResearch Institute for the Molecular Pathogeneses of Epilepsy, Fukuoka UniversityResearch Institute for the Molecular Pathogeneses of Epilepsy, Fukuoka UniversityDepartment of Neuropharmacology, Faculty of Pharmaceutical Sciences, Fukuoka UniversityDepartment of Neuropharmacology, Faculty of Pharmaceutical Sciences, Fukuoka UniversityResearch Institute for the Molecular Pathogeneses of Epilepsy, Fukuoka UniversityDepartment of Neuropharmacology, Faculty of Pharmaceutical Sciences, Fukuoka UniversityDepartment of Neuropharmacology, Faculty of Pharmaceutical Sciences, Fukuoka UniversityDepartment of Neuropharmacology, Faculty of Pharmaceutical Sciences, Fukuoka UniversityDepartment of Neuropharmacology, Faculty of Pharmaceutical Sciences, Fukuoka UniversityResearch Institute for the Molecular Pathogeneses of Epilepsy, Fukuoka UniversityAbstract Dravet syndrome (DS) is an intractable form of childhood epilepsy that occurs in infancy. More than 80% of all patients have a heterozygous abnormality in the SCN1A gene, which encodes a subunit of Na+ channels in the brain. However, the detailed pathogenesis of DS remains unclear. This study investigated the synaptic pathogenesis of this disease in terms of excitatory/inhibitory balance using a mouse model of DS. We show that excitatory postsynaptic currents were similar between Scn1a knock-in neurons (Scn1a +/− neurons) and wild-type neurons, but inhibitory postsynaptic currents were significantly lower in Scn1a +/− neurons. Moreover, both the vesicular release probability and the number of inhibitory synapses were significantly lower in Scn1a +/− neurons compared with wild-type neurons. There was no proportional increase in inhibitory postsynaptic current amplitude in response to increased extracellular Ca2+ concentrations. Our study revealed that the number of inhibitory synapses is significantly reduced in Scn1a +/− neurons, while the sensitivity of inhibitory synapses to extracellular Ca2+ concentrations is markedly increased. These data suggest that Ca2+ tethering in inhibitory nerve terminals may be disturbed following the synaptic burst, likely leading to epileptic symptoms.https://doi.org/10.1038/s41598-021-90224-4 |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Kouya Uchino Hiroyuki Kawano Yasuyoshi Tanaka Yuna Adaniya Ai Asahara Masanobu Deshimaru Kaori Kubota Takuya Watanabe Shutaro Katsurabayashi Katsunori Iwasaki Shinichi Hirose |
spellingShingle |
Kouya Uchino Hiroyuki Kawano Yasuyoshi Tanaka Yuna Adaniya Ai Asahara Masanobu Deshimaru Kaori Kubota Takuya Watanabe Shutaro Katsurabayashi Katsunori Iwasaki Shinichi Hirose Inhibitory synaptic transmission is impaired at higher extracellular Ca2+ concentrations in Scn1a +/− mouse model of Dravet syndrome Scientific Reports |
author_facet |
Kouya Uchino Hiroyuki Kawano Yasuyoshi Tanaka Yuna Adaniya Ai Asahara Masanobu Deshimaru Kaori Kubota Takuya Watanabe Shutaro Katsurabayashi Katsunori Iwasaki Shinichi Hirose |
author_sort |
Kouya Uchino |
title |
Inhibitory synaptic transmission is impaired at higher extracellular Ca2+ concentrations in Scn1a +/− mouse model of Dravet syndrome |
title_short |
Inhibitory synaptic transmission is impaired at higher extracellular Ca2+ concentrations in Scn1a +/− mouse model of Dravet syndrome |
title_full |
Inhibitory synaptic transmission is impaired at higher extracellular Ca2+ concentrations in Scn1a +/− mouse model of Dravet syndrome |
title_fullStr |
Inhibitory synaptic transmission is impaired at higher extracellular Ca2+ concentrations in Scn1a +/− mouse model of Dravet syndrome |
title_full_unstemmed |
Inhibitory synaptic transmission is impaired at higher extracellular Ca2+ concentrations in Scn1a +/− mouse model of Dravet syndrome |
title_sort |
inhibitory synaptic transmission is impaired at higher extracellular ca2+ concentrations in scn1a +/− mouse model of dravet syndrome |
publisher |
Nature Publishing Group |
series |
Scientific Reports |
issn |
2045-2322 |
publishDate |
2021-05-01 |
description |
Abstract Dravet syndrome (DS) is an intractable form of childhood epilepsy that occurs in infancy. More than 80% of all patients have a heterozygous abnormality in the SCN1A gene, which encodes a subunit of Na+ channels in the brain. However, the detailed pathogenesis of DS remains unclear. This study investigated the synaptic pathogenesis of this disease in terms of excitatory/inhibitory balance using a mouse model of DS. We show that excitatory postsynaptic currents were similar between Scn1a knock-in neurons (Scn1a +/− neurons) and wild-type neurons, but inhibitory postsynaptic currents were significantly lower in Scn1a +/− neurons. Moreover, both the vesicular release probability and the number of inhibitory synapses were significantly lower in Scn1a +/− neurons compared with wild-type neurons. There was no proportional increase in inhibitory postsynaptic current amplitude in response to increased extracellular Ca2+ concentrations. Our study revealed that the number of inhibitory synapses is significantly reduced in Scn1a +/− neurons, while the sensitivity of inhibitory synapses to extracellular Ca2+ concentrations is markedly increased. These data suggest that Ca2+ tethering in inhibitory nerve terminals may be disturbed following the synaptic burst, likely leading to epileptic symptoms. |
url |
https://doi.org/10.1038/s41598-021-90224-4 |
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