Tremendous efforts have been made to sequence DNA from large numbers of individuals with autism spectrum disorder (ASD) and hundreds of genes are now linked to ASD. Many of these genes support brain communication by controlling excitatory (glutamatergic) synapse development and function. Recent work by SFARI Investigator Bruce Herring provides further support for the idea that mutations in ASD risk genes lead to disruptions in these processes.
A prior study from Herring’s lab uncovered a number of human ASD-related mutations in a gene called Trio. They showed, in rodent culture systems, that these mutations altered the development of excitatory synapses in the brain (Sadybekov et al., Nat. Commun., 2017). One particular Trio mutation (D1368V) caused much more synapse formation than normal and increased overall neuronal communication in their model systems. Now, in work supported in part by a SFARI Pilot Award, Herring’s lab reports that Trio’s interactions with another known ASD-risk gene — NLGN1 — are key to Trio’s effects (Tian et al., J. Neurosci., 2021).
In this new study, Herring’s group showed that another ASD-linked Trio mutation (N1080I) prevented the hyperactivity caused by the Trio D1368V mutation. To understand what was causing these changes, biochemical and electrophysiology work was done in cell lines and rat brain cultures. Findings indicate that both the activity increases by the D1368V Trio mutation and the activity block by the N1080I Trio mutation involve changes in the way Trio interacts with NLGN1.
NLGN1 is known to play a role in making and stabilizing new excitatory synapses. The team found that Trio proteins with the N1080I mutation were not able to bind to NLGN1. This prevented NLGN1 from performing its role in synapse formation and reduced synapse communication. In contrast, the Trio D1368V mutation increased NLGN1 signaling within neurons. This led to an increase in synapses and an overactive brain. Combined, these data support the idea that disruptions to excitatory synapse development and maintenance are a key cause of ASD.
Autism spectrum disorder/intellectual disability-associated mutations in trio disrupt neuroligin 1-mediated synaptogenesis.
Tian C., Paskus J.D., Fingleton E., Roche K.W., Herring B. E.