Open AccessA GluN2B mutation identified in Autism prevents NMDA receptor trafficking and interferes with dendrite growth
Author(s) -
Michael P. Sceniak,
Karlie N. Fedder,
Qian Wang,
Sammy Droubi,
Katie Babcock,
Sagar Patwardhan,
Jazmin Wright-Zornes,
Lucynda Pham,
Shasta L. Sabo
Publication year - 2019
Publication title -
journal of cell science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.384
H-Index - 278
eISSN - 1477-9137
pISSN - 0021-9533
DOI - 10.1242/jcs.232892
Subject(s) - biology , mutant , mutation , phenotype , nmda receptor , dendrite (mathematics) , genetics , microbiology and biotechnology , neuroscience , receptor , gene , geometry , mathematics
Autism spectrum disorders (ASD) are neurodevelopmental disorders with multiple genetic associations. Analysis of de novo mutations identified GRIN2B, which encodes the GluN2B subunit of NMDA receptors, as a high-probability ASD gene. However, the mechanisms by which GRIN2B mutations contribute to ASD pathophysiology are not understood. Here, we investigated the cellular phenotypes induced by a human mutation that is predicted to truncate GluN2B within the extracellular loop. This mutation abolished NMDA-dependent calcium influx. Mutant GluN2B co-assembled with GluN1 but was not trafficked to the cell surface or dendrites. When mutant GluN2B was expressed in developing cortical neurons, dendrites appeared underdeveloped, with shorter and fewer branches, while spine density was unaffected. Mutant dendritic arbors were often dysmorphic, displaying abnormal filopodial-like structures. Interestingly, dendrite maldevelopment appeared when mutant GluN2B was expressed on a wild-type background, reflecting the disease as individuals are heterozygous for GRIN2B mutations. Restoring the fourth transmembrane domain and cytoplasmic tail did not rescue the phenotypes. Finally, abnormal development was not accompanied by reduced mTOR signaling. These data suggest that mutations in GRIN2B/GluN2B contribute to ASD pathogenesis by disrupting dendrite development.