Description:

"Synaptic dysfunction underlying neurodevelopmental disorders"

Human genetics studies have revealed that mutations in synaptic genes play a central role in the etiology of neurodevelopmental disorders such as autism spectrum disorder (ASD) and intellectual disability (ID). The highest confidence genes include those encoding proteins central to the development and function of excitatory synapses including NMDA receptors, scaffolding proteins, and cell adhesion molecules. Our group examines autism-associated mutations in NMDA receptors and neuroligins. We have focused on variants found in the C-terminal domains (CTD) of the NMDA receptor subunits GRIN2A and GRIN2B. Although the CTD tolerates more genetic variation compared to the ligand binding domain, this region is critical for NMDA receptor trafficking and localization at the synapse. We find that several CTD variants result in disruptions in binding to scaffolding proteins and deficits in NMDA receptor trafficking. Among the synaptic proteins most strongly associated with ASD/ID are the postsynaptic neuroligins (NLGN1-3, 4X, and 4Y) and their presynaptic binding partners, neurexins. In humans, both NLGN3 and NLGN4X are on the X chromosome and both have many variants associated with ASD/ID. Using information from public databases, as well as two newly identified probands, we recently demonstrated that there is a cluster of ASD-associated NLGN4X variants in the extracellular domain of NLGN4X. Importantly, NLGN4Y cannot compensate for the functional deficits observed in ASD-associated NLGN4X mutations, revealing a potential pathogenic mechanism for male bias in NLGN4X-associated ASD. We are currently conducting a small molecule screen to identify potential drug targets to relieve the trafficking deficit. We hope that our studies of synaptic dysfunction will allow for more translational approaches to studying neurodevelopmental disorders.

Thursday May 18, 2023  
CAN Seminar Series 
2:00 PM - 3:00 PM  
Location: Ward 5-230

Katherine Roche, PhD
Senior Investigator
Receptor Biology Section
NIH/NINDS