A Neuroligin-3 Mutation Implicated in Autism Increases Inhibitory Synaptic Transmission in Mice

TLDR

Autism spectrum disorders involve social impairments and sometimes enhanced cognition, and a minority of patients harbor neuroligin gene mutations. The study generated a neuroligin‑3 Arg451Cys knock‑in mouse model. R451C knock‑in mice displayed social deficits, improved spatial learning, and heightened inhibitory synaptic transmission without affecting excitatory synapses, indicating a gain‑of‑function mutation that may underlie autism and provides a useful model.

Abstract

Autism spectrum disorders (ASDs) are characterized by impairments in social behaviors that are sometimes coupled to specialized cognitive abilities. A small percentage of ASD patients carry mutations in genes encoding neuroligins, which are postsynaptic cell-adhesion molecules. We introduced one of these mutations into mice: the Arg451-->Cys451 (R451C) substitution in neuroligin-3. R451C mutant mice showed impaired social interactions but enhanced spatial learning abilities. Unexpectedly, these behavioral changes were accompanied by an increase in inhibitory synaptic transmission with no apparent effect on excitatory synapses. Deletion of neuroligin-3, in contrast, did not cause such changes, indicating that the R451C substitution represents a gain-of-function mutation. These data suggest that increased inhibitory synaptic transmission may contribute to human ASDs and that the R451C knockin mice may be a useful model for studying autism-related behaviors.