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 Tanaka, Shigeo Okabe, Katsuhiko Tabuchi, Takeshi Uemura, Masayoshi Mishina, Hisashi Mori and Shuya Fukai ()
Additional contact information
Tomoyuki Yoshida: University of Toyama
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
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
Hisao Nishijo: University of Toyama
Keizo Takao: University of Toyama
Shinji Tanaka: The University of Tokyo
Shigeo Okabe: The University of Tokyo
Katsuhiko Tabuchi: JST PRESTO
Takeshi Uemura: Shinshu University
Masayoshi Mishina: Ritsumeikan University
Hisashi Mori: University of Toyama
Shuya Fukai: Kyoto University

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: 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.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-22059-6

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DOI: 10.1038/s41467-021-22059-6

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