Canonical versus non-canonical transsynaptic signaling of neuroligin 3 tunes development of sociality in mice

Tomoyuki Yoshida*, Atsushi Yamagata, Ayako Imai, Juhyon Kim, Hironori Izumi, Shogo Nakashima, Tomoko Shiroshima, Asami Maeda, Shiho Iwasawa-Okamoto, Kenji Azechi, Fumina Osaka, Takashi Saitoh, Katsumi Maenaka, Takashi Shimada, Yuko Fukata, Masaki Fukata, Jumpei Matsumoto, Hisao Nishijo, Keizo Takao, Shinji TanakaShigeo Okabe, Katsuhiko Tabuchi, Takeshi Uemura, Masayoshi Mishina, Hisashi Mori, Shuya Fukai*

*この論文の責任著者

研究成果: ジャーナルへの寄稿学術論文査読

28 被引用数 (Scopus)

抄録

Neuroligin 3 (NLGN3) and neurexins (NRXNs) constitute a canonical transsynaptic cell-adhesion pair, which has been implicated in autism. In autism spectrum disorder (ASD) development of sociality can be impaired. However, the molecular mechanism underlying NLGN3-mediated social development is unclear. Here, we identify non-canonical interactions between NLGN3 and protein tyrosine phosphatase δ (PTPδ) splice variants, competing with NRXN binding. NLGN3-PTPδ complex structure revealed a splicing-dependent interaction mode and competition mechanism between PTPδ and NRXNs. Mice carrying a NLGN3 mutation that selectively impairs NLGN3-NRXN interaction show increased sociability, whereas mice where the NLGN3-PTPδ interaction is impaired exhibit impaired social behavior and enhanced motor learning, with imbalance in excitatory/inhibitory synaptic protein expressions, as reported in the Nlgn3 R451C autism model. At neuronal level, the autism-related Nlgn3 R451C mutation causes selective impairment in the non-canonical pathway. Our findings suggest that canonical and non-canonical NLGN3 pathways compete and regulate the development of sociality.

本文言語英語
論文番号1848
ジャーナルNature Communications
12
1
DOI
出版ステータス出版済み - 2021/12/01

ASJC Scopus 主題領域

  • 化学一般
  • 生化学、遺伝学、分子生物学一般
  • 物理学および天文学一般

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