Canonical versus non-canonical transsynaptic signaling of neuroligin 3 tunes development of sociality in mice
Open accessAbstract
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.
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Mutations in neuroligins and neurexins have been repeatedly linked to non-syndromic ASD and related neurodevelopmental conditions.
“Mutations in neuroligins and neurexins have been repeatedly linked to non-syndromic ASD and related neurodevelopmental conditions (Yoshida et al., 2021).”
From Biological hierarchy from genotype to phenotype in syndromic and non-syndromic autism spectrum disorder (2026) · cites this paper as Yoshida et al., 2021
The Introduction (page unavailable) links multiple NLGN3 mutations to ASD and says NRXN1 mutations have been detected in people with ASD and may predispose to a wider range of neurodevelopmental and psychiatric disorders. It does not specify non-syndromic ASD, and its discussion of neurexin mutations is limited to NRXN1 rather than neurexins generally. (LLM, conf=0.87)
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References 63 · Cited by 50
- Authors
- Yoshida, T., Yamagata, A., Imai, A., Kim, J., Izumi, H., Nakashima, S., Shiroshima, T., Maeda, A., Iwasawa-Okamoto, S., Azechi, K., Osaka, F., Saitoh, T., Maenaka, K., Shimada, T., Fukata, Y., Fukata, M., Matsumoto, J., Nishijo, H., Takao, K., Tanaka, S., Okabe, S., Tabuchi, K., Uemura, T., Mishina, M., Mori, H., & Fukai, S.
- Affiliations
- Japan Science and Technology Agency (JP)
- RIKEN Center for Biosystems Dynamics Research (JP)
- University of Toyama (JP)
- Kitasato University (JP)
- Juntendo University (JP)
- Hokkaido University (JP)
- National Institutes of Natural Sciences (JP)
- The University of Tokyo (JP)
- Shinshu University (JP)
- Ritsumeikan University (JP)
- Kyoto University (JP)
- Corresponding author
- Yoshida, Tomoyuki
- Fukai, Shuya
- ORCID
- Venue
- Nature Communications
- Published
- 2021-03-23
- Volume
- 12
- Issue
- 1
- Pages
- 1848-1848
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC7988105
- OpenAlex
- W3138727301
- Cited by
- 50
- References
- 63
- Citations by year
- 2026: 10 · 2025: 9 · 2024: 8 · 2023: 12 · 2022: 7 · 2021: 4
- FWCI
- 4.52
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Institutional Repositories DataBase (IRDB) (submittedVersion, cc-by)
- Kyoto University Research Information Repository (Kyoto University) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- MEXT | Japan Society for the Promotion of Science (JP25293057, JP19H04744, JP20H03350, JP16H06276, JP16H04749, JP19K19407, JP16H06534, JP16H04676, JP24247014)
- MEXT | JST | Precursory Research for Embryonic Science and Technology
- Takeda Science Foundation
- MEXT | JST | Core Research for Evolutional Science and Technology (JPMJCR12M5)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- neuroligin-3, neurexin, trans-synaptic signaling, splice variants, social behavior, autism spectrum disorder, motor learning, excitation-inhibition balance, synaptic proteins, adhesion molecules, mice
- MeSH terms
- Behavior Rating Scale, Autism Spectrum Disorder, Protein Domains, Amino Acid Sequence, Animals, Calcium-Binding Proteins, Disease Models, Animal, Female, Humans, Male, Membrane Proteins, Mice, Transgenic, Mutation, Nerve Tissue Proteins, Neurons, Recombinant Proteins, Social Behavior, Synapses, Signal Transduction, Cell Adhesion Molecules, Neuronal, Mice, Knockout, Neural Cell Adhesion Molecules, Protein Splicing, Mice, Receptor-Like Protein Tyrosine Phosphatases, Class 2, HEK293 Cells
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