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

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

doi:10.1038/s41467-021-22059-6

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.

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

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