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.
Highlights
Social behaviors for properly communicating with others are mediated by various cortical and subcortical neural circuits, including the medial prefrontal cortex, amygdala, anterior insula, anterior cingulate cortex, inferior frontal gyrus, and superior temporal sulcus
We identified an interaction between PTPδ and neuroligin 3 (NLGN3), one of the best-characterized postsynaptic binding partners of NRXNs39,40
Our structural analyses suggest that the deletion of the meB peptide confines the spacing between Ig2 and Ig3 of PTPδ for simultaneous interaction with NLGN3, whereas the meA3 peptide in PTPδ Ig2 contributes to direct hydrophobic interaction with the C-terminal tail of the NLGN3 extracellular domains (ECDs)
Summary
Social behaviors for properly communicating with others are mediated by various cortical and subcortical neural circuits, including the medial prefrontal cortex (mPFC), amygdala, anterior insula, anterior cingulate cortex, inferior frontal gyrus, and superior temporal sulcus. The signal intensities for Shank[2] and gephyrin were dependent on the size of the meA peptides, i.e., the longer the meA peptides, the greater the accumulation of the postsynaptic proteins on the beads These results suggest that PTPδ-meB(+)s selectively induce the excitatory postsynaptic differentiation, whereas PTPδ-meB(–)s are involved in both excitatory and inhibitory postsynaptic differentiation. The excitatory postsynaptic differentiation induced by PTPδA9B+, a PTPδ-meB(+) isoform abundantly expressed in the developing mouse brain[20], was reduced by ~70% in cultured cortical neurons from IL1RAPL1/IL-1RAcP double-knockout (DKO) mice (Supplementary Fig. 1a, b), suggesting IL1RAPL1 and IL-1RAcP are major postsynaptic ligands for PTPδA9B+ to induce excitatory synapse formation in the cortical neurons. Liquid chromatography-tandem mass spectrometry of the PTPδA3B– complex identified four transmembrane proteins, including NLGN3 (Supplementary Table 1)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
