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

被引:26
作者
Yoshida, Tomoyuki [1 ,2 ,3 ]
Yamagata, Atsushi [4 ]
Imai, Ayako [1 ]
Kim, Juhyon [5 ]
Izumi, Hironori [1 ]
Nakashima, Shogo [6 ]
Shiroshima, Tomoko [7 ]
Maeda, Asami [8 ]
Iwasawa-Okamoto, Shiho [1 ]
Azechi, Kenji [1 ]
Osaka, Fumina [9 ]
Saitoh, Takashi [9 ]
Maenaka, Katsumi [9 ,10 ]
Shimada, Takashi [11 ]
Fukata, Yuko [12 ]
Fukata, Masaki [12 ]
Matsumoto, Jumpei [2 ,6 ]
Nishijo, Hisao [2 ,6 ]
Takao, Keizo [2 ,13 ]
Tanaka, Shinji [14 ]
Okabe, Shigeo [14 ]
Tabuchi, Katsuhiko [3 ,15 ,16 ]
Uemura, Takeshi [16 ,17 ]
Mishina, Masayoshi [18 ]
Mori, Hisashi [1 ,2 ]
Fukai, Shuya [19 ]
机构
[1] Toyama Univ, Dept Mol Neurosci, Fac Med, Toyama, Japan
[2] Toyama Univ, Res Ctr Idling Brain Sci, Toyama, Japan
[3] JST PRESTO, Saitama, Japan
[4] RIKEN, Ctr Biosyst Dynam Res, Kanagawa, Japan
[5] Toyama Univ, Div Bio Informat Engn, Fac Engn, Toyama, Japan
[6] Toyama Univ, Dept Syst Emot Sci, Fac Med, Toyama, Japan
[7] Kitasato Univ, Dept Anat, Sch Med, Kanagawa, Japan
[8] Juntendo Univ, Res Inst Dis Old Age, Grad Sch Med, Tokyo, Japan
[9] Hokkaido Univ, Fac Pharmaceut Sci, Ctr Res & Educ Drug Discovery, Sapporo, Hokkaido, Japan
[10] Hokkaido Univ, Fac Pharmaceut Sci, Lab Biomol Sci, Sapporo, Hokkaido, Japan
[11] Shimadzu Sci Instruments, Innovat Ctr, SHIMADZU Biosci Res Partnership, Bothell, WA USA
[12] Natl Inst Physiol Sci, Dept Mol & Cellular Physiol, Div Membrane Physiol, Aichi, Japan
[13] Toyama Univ, Life Sci Res Ctr, Toyama, Japan
[14] Univ Tokyo, Grad Sch Med, Dept Cellular Neurobiol, Tokyo, Japan
[15] Shinshu Univ, Inst Med Acad Assembly, Dept Mol & Cellular Physiol, Nagano, Japan
[16] Shinshu Univ, Inst Biomed Sci, Interdisciplinary Cluster Cutting Edge Res, Nagano, Japan
[17] Shinshu Univ, Res Ctr Supports Adv Sci, Div Gene Res, Nagano, Japan
[18] Ritsumeikan Univ, Brain Sci Lab, Res Org Sci & Technol, Shiga, Japan
[19] Kyoto Univ, Grad Sch Sci, Dept Chem, Kyoto, Japan
关键词
MEDIATES SYNAPSE FORMATION; RARE DE-NOVO; AUTISM; PROTEIN; NEUREXIN; MUTATIONS; DOMAIN; BEHAVIOR; ABNORMALITIES; GLUR-DELTA-2;
D O I
10.1038/s41467-021-22059-6
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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 delta (PTP delta) splice variants, competing with NRXN binding. NLGN3-PTP delta complex structure revealed a splicing-dependent interaction mode and competition mechanism between PTP delta and NRXNs. Mice carrying a NLGN3 mutation that selectively impairs NLGN3-NRXN interaction show increased sociability, whereas mice where the NLGN3-PTP delta 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. Mutations of Neuroligin 3 (NLGN3) have been associated with autism spectrum disorder (ASD). Here, the authors identify a previously undescribed interaction between NLGN3 and a splice variant of protein tyrosine phosphatase delta (PTP delta) and its role in development of social behaviour in mice.
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页数:15
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