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

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.

Neuroligin-3: A Circuit-Specific Synapse Organizer That Shapes Normal Function and Autism Spectrum Disorder-Associated Dysfunction

“…Importantly, the presence or absence of the splice insertions A1 and A2 play roles in synaptic function as described previously (Philibert et al, 2000;Oku et al, 2020;Uchigashima et al, 2020b). The extracellular cholinesterase-like domain also has the Nlgn-Nlgn dimerization interface which is highly conserved among different Nlgn isoforms (Dean et al, 2003;Arac et al, 2007;Yoshida et al, 2021).…”

“…Nlgn3 molecule forms homodimers and heterodimers with other Nlgn isoforms in the secretory pathway and translocate to the plasma membrane (Poulopoulos et al, 2012;Yoshida et al, 2021). Nlgn1 protein can participate in the heterodimerization with Nlgn3 (Poulopoulos et al, 2012).…”

“…All Nlgn3 splice isoforms exhibit a higher binding affinity to βNrxn without the insertion of AS4 than those with AS4 (Ichtchenko et al, 1996;Koehnke et al, 2010). Structural analysis predicts the βNrxn1 binding site of Nlgn3 protein is composed of H279-E281, N362, and Q370-N377 (Yoshida et al, 2021). The ASD-associated R451C mutation on the extracellular domain can interfere with this binding (Comoletti et al, 2004;Yoshida et al, 2021).…”

“…Structural analysis predicts the βNrxn1 binding site of Nlgn3 protein is composed of H279-E281, N362, and Q370-N377 (Yoshida et al, 2021). The ASD-associated R451C mutation on the extracellular domain can interfere with this binding (Comoletti et al, 2004;Yoshida et al, 2021). Nlgn3 can also bind to αNrxn1 protein regardless of the presence or absence of the splice insertion at AS4 (Boucard et al, 2005).…”

“…Nrxn has been considered the sole presynaptic binding partner of Nlgn for decades, however, a recent study identified Nlgn3 as a selective ligand for presynaptically-expressed type IIA receptor protein tyrosine phosphatase delta (PTPδ) (Yoshida et al, 2021). Similar to Nrxn genes, PTPδ has multiple isoforms generated by alternative splicing of microexons (Takahashi and Craig, 2013).…”