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

Publication date: 29 May 2018
Source:Cell Reports, Volume 23, Issue 9
Author(s): Kira V. Gromova, Mary Muhia, Nicola Rothammer, Christine E. Gee, Edda Thies, Irina Schaefer, Sabrina Kress, Manfred W. Kilimann, Olga Shevchuk, Thomas G. Oertner, Matthias Kneussel
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.

Graphical abstract

Teaser

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.


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