Neuroligin 3 Regulates Dendritic Outgrowth by Modulating Akt/mTOR Signaling

Abstract

Neuroligins (NLs) are a group of postsynaptic cell adhesion molecules that function in synaptogenesis and synaptic transmission. Genetic defects in neuroligin 3 (NL3), a member of the NL protein family, are associated with autism. Studies in rodents have revealed that mutations of NL3 gene lead to increased growth and complexity in dendrites in the central nervous system. However, the detailed mechanism is still unclear. In our study, we found that deficiency of NL3 led to morphological changes of the pyramidal neurons in layer II/III somatosensory cortex in mice, including enlarged somata, elongated dendritic length, and increased dendritic complexity. Knockdown of NL3 in cultured rat neurons upregulated Akt/mTOR signaling, resulting in both increased protein synthesis and dendritic growth. Treating neurons with either rapamycin to inhibit the mTOR or LY294002 to inhibit the PI3K/Akt activity rescued the morphological abnormalities resulting from either NL3 knockdown or knockout (KO). In addition, we found that the hyperactivated Akt/mTOR signaling associated with NL3 defects was mediated by a reduction in phosphatase and tensin (PTEN) expression, and that MAGI-2, a scaffold protein, interacted with both NL3 and PTEN and could be a linker between NL3 and Akt/mTOR signaling pathway. In conclusion, our results suggest that NL3 regulates neuronal morphology, especially dendritic outgrowth, by modulating the PTEN/Akt/mTOR signaling pathway, probably via MAGI-2. Thereby, this study provides a new link between NL3 and neuronal morphology.

Rescue of oxytocin response and social behaviour in a mouse model of autism

“…Gene ontology (GO) and network-based functional classification analysis for proteins altered in Nlgn3 KO VTA identified protein transport, cell adhesion, and mRNA translation as main categories ( Extended Data Fig.4b,c ). Dysregulation of membrane trafficking and GPCR signaling components is consistent with the previously discovered roles for Nlgn3 in synapse organization and GPCR signaling 22 , 23 , 34 . However, the alterations in regulators of translation were surprising.…”

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

“…These results clearly indicate that Nlgn3 is not just synaptic glue but acts as a synaptic regulator. Indeed, Nlgn3 regulates dendritic structure by modulating mTOR signaling (Xu et al, 2019) and Nlgn3 KO caused dysregulation of mGluR-dependent signaling (Baudouin et al, 2012;but see Rothwell et al, 2014;Zhang et al, 2015). These studies support the profound importance of Nlgn3 as an upstream regulator of translational pathways vulnerable in ASD.…”

Protein synthesis as a modifiable target for autism‐related dendritic spine pathophysiologies

“…Hörnberg et al demonstrated that Neuroligin3-knockout mice exhibit an impaired response to oxytocin and hyperactive translation in dopaminergic neurons at the ventral tegmental area (VTA), but suppressing translation with the MNK1/2 inhibitor ETC-168 rescued the oxytocin response and ameliorated ASD-like behaviors [83]. Intriguingly, dendritic outgrowth and protein synthesis were previously shown to be globally enhanced in Neuroligin3-knockout rats, though dendritic spine density was not directly measured [84].…”