Neurobeachin and the Kinesin KIF21B Are Critical for Endocytic Recycling of NMDA Receptors and Regulate Social Behavior

Autism spectrum disorders (ASDs) are associated with mutations affecting synaptic components, including GluN2B-NMDA receptors (NMDARs) and neurobeachin (NBEA). NBEA participates in biosynthetic pathways to regulate synapse receptor targeting, synaptic function, cognition, and social behavior. However, the role of NBEA-mediated transport in specific trafficking routes is unclear. Here, we highlight an additional function for NBEA in the local delivery and surface re-insertion of synaptic receptors in mouse neurons. NBEA dynamically interacts with Rab4-positive recycling endosomes, transiently enters spines in an activity-dependent manner, and regulates GluN2B-NMDAR recycling. Furthermore, we show that the microtubule growth inhibitor kinesin KIF21B constrains NBEA dynamics and is present in the NBEA-recycling endosome-NMDAR complex. Notably, Kif21b knockout decreases NMDAR surface expression and alters social behavior in mice, consistent with reported social deficits in Nbea mutants. The influence of NBEA-KIF21B interactions on GluN2B-NMDAR local recycling may be relevant to mechanisms underlying ASD etiology. [Display omitted] •NBEA associates with endosomal recycling factors and labels tubules at endosomes•NBEA transiently enters synapses and is regulated by KIF21B and dynein motors•NBEA and KIF21B regulate GluN2B-containing NMDA receptor cell surface expression•Similar to NBEA, KIF21B is relevant for ASD-related social behavior Gromova et al. functionally link the autism risk factor neurobeachin with KIF21B and endosomal pathways. Dynamic NBEA localizes at recycling endosomes and enters synapses in an activity-dependent manner. NBEA and KIF21B regulate NMDAR cell surface expression, and similar to NBEA mutants, KIF21B depletion induces social abnormalities linked to autism.