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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Autores principales:	Kouya Uchino, Hiroyuki Kawano, Yasuyoshi Tanaka, Yuna Adaniya, Ai Asahara, Masanobu Deshimaru, Kaori Kubota, Takuya Watanabe, Shutaro Katsurabayashi, Katsunori Iwasaki, Shinichi Hirose
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/f6e6c8cce3c4492e8c1aea934931d3d8
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spelling	oai:doaj.org-article:f6e6c8cce3c4492e8c1aea934931d3d82021-12-02T16:49:37ZInhibitory synaptic transmission is impaired at higher extracellular Ca2+ concentrations in Scn1a +/− mouse model of Dravet syndrome10.1038/s41598-021-90224-42045-2322https://doaj.org/article/f6e6c8cce3c4492e8c1aea934931d3d82021-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-90224-4https://doaj.org/toc/2045-2322Abstract 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.Kouya UchinoHiroyuki KawanoYasuyoshi TanakaYuna AdaniyaAi AsaharaMasanobu DeshimaruKaori KubotaTakuya WatanabeShutaro KatsurabayashiKatsunori IwasakiShinichi HiroseNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q 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
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.
format	article
author	Kouya Uchino Hiroyuki Kawano Yasuyoshi Tanaka Yuna Adaniya Ai Asahara Masanobu Deshimaru Kaori Kubota Takuya Watanabe Shutaro Katsurabayashi Katsunori Iwasaki Shinichi Hirose
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 Portfolio
publishDate	2021
url	https://doaj.org/article/f6e6c8cce3c4492e8c1aea934931d3d8
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Inhibitory synaptic transmission is impaired at higher extracellular Ca2+ concentrations in Scn1a +/− mouse model of Dravet syndrome

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