Neuroligins (NLGNs) are evolutionarily conserved cell adhesion proteins that mediate the formation of synapses between neurons. NLGNs are genetically linked to autism and perform essential functions at synapses, which are specialized neuronal junctions that allow neurons to talk to each other. More than 50 independent mutations in NLGN genes have been associated with autism in human genetics studies. In the literature, all individuals with NLGN mutations exhibit symptoms of autism, suggesting 100 percent ‘penetrance’ — the proportion of individuals with the mutation who exhibit symptoms.
Although autism cases caused by NLGN mutations are extremely rare, their high degree of penetrance and the potential for understanding how such mutations cause brain dysfunction provide an opportunity to learn more about the pathogenesis of autism by analyzing the effects of autism-associated NLGN mutations on brain function. Thomas Südhof and his colleagues at Stanford University School of Medicine in California aimed to use mice as models to elucidate what NLGNs normally do at a synapse, how mutations in NLGNs that predispose to autism affect synaptic function and by which mechanisms these mutations alter synapses.
Südhof and his group analyzed the biochemical properties of NLGNs, generated conditional knockout mice for NLGN genes that are expressed at significant levels in rodents and performed initial analyses on the effect of autism-associated mutations in NLGNs on mouse behavior and synaptic function.
NLGNs perform a much larger diversity of functions in the brain than anticipated, and they interact with more binding partners in performing these functions than previously known. Although these results corroborate the central role of NLGNs in synapse formation and function, they also demonstrate that the diversity of NLGN function is incompletely understood. These results suggest that definitive insights into how NLGN mutations produce autism will require identification of the specific circuit abnormalities that are produced by synaptic dysfunction induced by the NLGN mutations.