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

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  • Shin‐ichiro Horigane
    Department of Neuroscience I Research Institute of Environmental Medicine Nagoya University Nagoya Japan
  • Yukihiro Ozawa
    Department of Neuroscience I Research Institute of Environmental Medicine Nagoya University Nagoya Japan
  • Jun Zhang
    Department of Neuroscience I Research Institute of Environmental Medicine Nagoya University Nagoya Japan
  • Hiroe Todoroki
    Laboratory for Systems Neurosciences and Preventive Medicine Faculty of Human Sciences Waseda University Tokorozawa Japan
  • Pan Miao
    Department of Neuroscience I Research Institute of Environmental Medicine Nagoya University Nagoya Japan
  • Asahi Haijima
    Laboratory for Systems Neurosciences and Preventive Medicine Faculty of Human Sciences Waseda University Tokorozawa Japan
  • Yuchio Yanagawa
    Department of Genetic and Behavioral Neuroscience Gunma University Graduate School of Medicine Maebashi Japan
  • Shuhei Ueda
    Department of Neuroscience I Research Institute of Environmental Medicine Nagoya University Nagoya Japan
  • Shigeo Nakamura
    Department of Pathology and Laboratory Medicine Nagoya University Hospital Nagoya Japan
  • Masaki Kakeyama
    Laboratory for Systems Neurosciences and Preventive Medicine Faculty of Human Sciences Waseda University Tokorozawa Japan
  • Sayaka Takemoto‐Kimura
    Department of Neuroscience I Research Institute of Environmental Medicine Nagoya University Nagoya Japan

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Description

<jats:p>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<jats:sup>2+</jats:sup> channels, Ca<jats:sub>v</jats:sub>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.</jats:p>

Journal

  • FEBS Open Bio

    FEBS Open Bio 10 (8), 1436-1446, 2020-07-19

    Wiley

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