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

来源：

NATURE COMMUNICATIONS | 2021年 / 12卷 / 01期

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.

引用

页数：15

共 64 条

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