Perturbed Hippocampal Synaptic Inhibition and γ-Oscillations in a Neuroligin-4 Knockout Mouse Model of Autism

Loss-of-function mutations in the synaptic adhesion protein Neuroligin-4 are among the most common genetic abnormalities associated with autism spectrum disorders, but little is known about the function of Neuroligin-4 and the consequences of its loss. We assessed synaptic and network characteristics in Neuroligin-4 knockout mice, focusing on the hippocampus as a model brain region with a critical role in cognition and memory, and found that Neuroligin-4 deletion causes subtle defects of the protein composition and function of GABAergic synapses in the hippocampal CA3 region. Interestingly, these subtle synaptic changes are accompanied by pronounced perturbations of γ-oscillatory network activity, which has been implicated in cognitive function and is altered in multiple psychiatric and neurodevelopmental disorders. Our data provide important insights into the mechanisms by which Neuroligin-4-dependent GABAergic synapses may contribute to autism phenotypes and indicate new strategies for therapeutic approaches. [Display omitted] •Nlgn4 KO alters the composition of perisomatic inhibitory synapses in hippocampus•Inhibitory synaptic transmission is impaired in Nlgn4 KO hippocampal area CA3•Nlgn4 KO strongly perturbs oscillatory network activity in hippocampal area CA3•Altered GABAergic signaling may link Nlgn4 loss-of-function mutations to autism Hammer et al. show that deletion of autism-associated Nlgn4 alters the composition of mouse hippocampal perisomatic inhibitory synapses and inhibitory synaptic transmission. Strongly perturbed γ-oscillations in area CA3 of Nlgn4 KO mice may link Nlgn4 loss to cognitive dysfunction.