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

Author

Listed:
  • Tomoyuki Yoshida

    (University of Toyama
    University of Toyama
    JST PRESTO)

  • Atsushi Yamagata

    (RIKEN Center for Biosystems Dynamics Research)

  • Ayako Imai

    (University of Toyama)

  • Juhyon Kim

    (University of Toyama)

  • Hironori Izumi

    (University of Toyama)

  • Shogo Nakashima

    (University of Toyama)

  • Tomoko Shiroshima

    (Kitasato University School of Medicine)

  • Asami Maeda

    (Juntendo University Graduate School of Medicine)

  • Shiho Iwasawa-Okamoto

    (University of Toyama)

  • Kenji Azechi

    (University of Toyama)

  • Fumina Osaka

    (Hokkaido University)

  • Takashi Saitoh

    (Hokkaido University)

  • Katsumi Maenaka

    (Hokkaido University
    Hokkaido University)

  • Takashi Shimada

    (SHIMADZU Bioscience Research Partnership, Innovation Center, Shimadzu Scientific Instruments)

  • Yuko Fukata

    (National Institutes of Natural Sciences)

  • Masaki Fukata

    (National Institutes of Natural Sciences)

  • Jumpei Matsumoto

    (University of Toyama
    University of Toyama)

  • Hisao Nishijo

    (University of Toyama
    University of Toyama)

  • Keizo Takao

    (University of Toyama
    University of Toyama)

  • Shinji Tanaka

    (The University of Tokyo)

  • Shigeo Okabe

    (The University of Tokyo)

  • Katsuhiko Tabuchi

    (JST PRESTO
    Shinshu University
    Shinshu University)

  • Takeshi Uemura

    (Shinshu University
    Shinshu University)

  • Masayoshi Mishina

    (Ritsumeikan University)

  • Hisashi Mori

    (University of Toyama
    University of Toyama)

  • Shuya Fukai

    (Kyoto University)

Abstract

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.

Suggested Citation

  • Tomoyuki Yoshida & Atsushi Yamagata & Ayako Imai & Juhyon Kim & Hironori Izumi & Shogo Nakashima & Tomoko Shiroshima & Asami Maeda & Shiho Iwasawa-Okamoto & Kenji Azechi & Fumina Osaka & Takashi Saito, 2021. "Canonical versus non-canonical transsynaptic signaling of neuroligin 3 tunes development of sociality in mice," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-22059-6
    DOI: 10.1038/s41467-021-22059-6
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    Cited by:

    1. Alessandra Sclip & Thomas C. Südhof, 2023. "Combinatorial expression of neurexins and LAR-type phosphotyrosine phosphatase receptors instructs assembly of a cerebellar circuit," Nature Communications, Nature, vol. 14(1), pages 1-14, December.

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