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A mouse model of Timothy syndrome exhibits altered social competitive dominance and inhibitory neuron development

Multiple genetic factors related to autism spectrum disorder (ASD) have been identified, but the biological mechanisms remain obscure. Timothy syndrome (TS), associated with syndromic ASD, is caused by a gain‐of‐function mutation, G406R, in the pore‐forming subunit of L‐type Ca(2+) channels, Ca(v)1....

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Autores principales: Horigane, Shin‐ichiro, Ozawa, Yukihiro, Zhang, Jun, Todoroki, Hiroe, Miao, Pan, Haijima, Asahi, Yanagawa, Yuchio, Ueda, Shuhei, Nakamura, Shigeo, Kakeyama, Masaki, Takemoto‐Kimura, Sayaka
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7396430/
https://www.ncbi.nlm.nih.gov/pubmed/32598571
http://dx.doi.org/10.1002/2211-5463.12924
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author Horigane, Shin‐ichiro
Ozawa, Yukihiro
Zhang, Jun
Todoroki, Hiroe
Miao, Pan
Haijima, Asahi
Yanagawa, Yuchio
Ueda, Shuhei
Nakamura, Shigeo
Kakeyama, Masaki
Takemoto‐Kimura, Sayaka
author_facet Horigane, Shin‐ichiro
Ozawa, Yukihiro
Zhang, Jun
Todoroki, Hiroe
Miao, Pan
Haijima, Asahi
Yanagawa, Yuchio
Ueda, Shuhei
Nakamura, Shigeo
Kakeyama, Masaki
Takemoto‐Kimura, Sayaka
author_sort Horigane, Shin‐ichiro
collection PubMed
description Multiple genetic factors related to autism spectrum disorder (ASD) have been identified, but the biological mechanisms remain obscure. Timothy syndrome (TS), associated with syndromic ASD, is caused by a gain‐of‐function mutation, G406R, in the pore‐forming subunit of L‐type Ca(2+) channels, Ca(v)1.2. In this study, a mouse model of TS, TS2‐neo, was used to enhance behavioral phenotyping and to identify developmental anomalies in inhibitory neurons. Using the IntelliCage, which enables sequential behavioral tasks without human handling and mouse isolation stress, high social competitive dominance was observed in TS2‐neo mice. Furthermore, histological analysis demonstrated inhibitory neuronal abnormalities in the neocortex, including an excess of smaller‐sized inhibitory presynaptic terminals in the somatosensory cortex of young adolescent mice and higher numbers of migrating inhibitory neurons from the medial ganglionic eminence during embryonic development. In contrast, no obvious changes in excitatory synaptic terminals were found. These novel neural abnormalities in inhibitory neurons of TS2‐neo mice may result in a disturbed excitatory/inhibitory (E/I) balance, a key feature underlying ASD.
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spelling pubmed-73964302020-08-06 A mouse model of Timothy syndrome exhibits altered social competitive dominance and inhibitory neuron development Horigane, Shin‐ichiro Ozawa, Yukihiro Zhang, Jun Todoroki, Hiroe Miao, Pan Haijima, Asahi Yanagawa, Yuchio Ueda, Shuhei Nakamura, Shigeo Kakeyama, Masaki Takemoto‐Kimura, Sayaka FEBS Open Bio Research Articles Multiple genetic factors related to autism spectrum disorder (ASD) have been identified, but the biological mechanisms remain obscure. Timothy syndrome (TS), associated with syndromic ASD, is caused by a gain‐of‐function mutation, G406R, in the pore‐forming subunit of L‐type Ca(2+) channels, Ca(v)1.2. In this study, a mouse model of TS, TS2‐neo, was used to enhance behavioral phenotyping and to identify developmental anomalies in inhibitory neurons. Using the IntelliCage, which enables sequential behavioral tasks without human handling and mouse isolation stress, high social competitive dominance was observed in TS2‐neo mice. Furthermore, histological analysis demonstrated inhibitory neuronal abnormalities in the neocortex, including an excess of smaller‐sized inhibitory presynaptic terminals in the somatosensory cortex of young adolescent mice and higher numbers of migrating inhibitory neurons from the medial ganglionic eminence during embryonic development. In contrast, no obvious changes in excitatory synaptic terminals were found. These novel neural abnormalities in inhibitory neurons of TS2‐neo mice may result in a disturbed excitatory/inhibitory (E/I) balance, a key feature underlying ASD. John Wiley and Sons Inc. 2020-07-19 /pmc/articles/PMC7396430/ /pubmed/32598571 http://dx.doi.org/10.1002/2211-5463.12924 Text en © 2020 The Authors. Published by FEBS Press and John Wiley & Sons Ltd. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
Horigane, Shin‐ichiro
Ozawa, Yukihiro
Zhang, Jun
Todoroki, Hiroe
Miao, Pan
Haijima, Asahi
Yanagawa, Yuchio
Ueda, Shuhei
Nakamura, Shigeo
Kakeyama, Masaki
Takemoto‐Kimura, Sayaka
A mouse model of Timothy syndrome exhibits altered social competitive dominance and inhibitory neuron development
title A mouse model of Timothy syndrome exhibits altered social competitive dominance and inhibitory neuron development
title_full A mouse model of Timothy syndrome exhibits altered social competitive dominance and inhibitory neuron development
title_fullStr A mouse model of Timothy syndrome exhibits altered social competitive dominance and inhibitory neuron development
title_full_unstemmed A mouse model of Timothy syndrome exhibits altered social competitive dominance and inhibitory neuron development
title_short A mouse model of Timothy syndrome exhibits altered social competitive dominance and inhibitory neuron development
title_sort mouse model of timothy syndrome exhibits altered social competitive dominance and inhibitory neuron development
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7396430/
https://www.ncbi.nlm.nih.gov/pubmed/32598571
http://dx.doi.org/10.1002/2211-5463.12924
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