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

Shin ichiro Horigane, Yukihiro Ozawa, Jun Zhang, Hiroe Todoroki, Pan Miao, Asahi Haijima, Yuchio Yanagawa, Shuhei Ueda, Shigeo Nakamura, Masaki Kakeyama, Sayaka Takemoto-Kimura*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

Abstract

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 Ca2+ channels, Cav1.2. 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.

Original languageEnglish
Pages (from-to)1436-1446
Number of pages11
JournalFEBS Open Bio
Volume10
Issue number8
DOIs
Publication statusPublished - 2020 Aug 1

Keywords

  • IntelliCage
  • L-type Ca channels
  • Timothy syndrome
  • autism spectrum disorder
  • neural circuit formation
  • social competitive dominance

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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