An autism-associated mutation in GluN2B prevents NMDA receptor trafficking and interferes with dendrite growth

Abstract

Autism spectrum disorders (ASDs) are neurodevelopmental disorders with multiple genetic associations. Analysis of de novo mutations identified GRIN2B, which encodes the GluN2B subunit of NMDA receptors, as a gene linked to ASDs with high probability. 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 Ca 2+ 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 given that 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 GluN2B contribute to ASD pathogenesis by disrupting dendrite development.

GluN2B but Not GluN2A for Basal Dendritic Growth of Cortical Pyramidal Neurons

“…Other mental disorder-related mutants of GluN2B have been recently discovered. For instance, GluN2B truncated at position 724 assembles with GluN1 but fails to reach the plasma membrane, and overexpressing this mutant in dissociated rat cortical pyramidal neurons results at DIV 10-14 in dramatically stunted dendritic growth (Sceniak et al, 2019). Further, a recent study of transgenic mice expressing chimeric GluN2 subunits reports that overexpression of the GluN2A with the GluN2B C-terminus, but not N-terminus or transmembrane domains, results in longer dendrites of CA1 pyramidal neurons suggesting that particular aspects of intracellular, i.e., metabotropic signaling rather than the ion conductance per se causes these effects (Keith et al, 2019).…”

Changes in Serotonin Modulation of Glutamate Currents in Pyramidal Offspring Cells of Rats Treated With 5-MT during Gestation

“…[72], postulates that autism could be a hypoglutamatergic disorder; this is based on neuroanatomical and neuroimaging studies indicating alterations in regions rich in glutamatergic neurons, as well as the similarity of symptoms observed in autism and those produced by NMDA antagonists in healthy subjects. In support of this theory, variations of the gene encoding the GluN2B subunit, which does not allow for adequate trafficking and expression to the cell surface, have recently been found in some autistic and schizophrenic patients [73,74]. Concerning this, Yuen et al [75] demonstrated that activation of the 5-HT 1A receptor decreases the traffic and expression of the GluN2B subunit.…”

Dendrites of Neocortical Pyramidal Neurons: The Key to Understand Intellectual Disability

“…A striking example is represented by the mutations of the NMDA receptor subunits, whose consequence is represented either by loss or by gain of function, with possible excitotoxic mechanisms mediating the damage in the latter case (Lemke et al 2016;Fry et al 2018). NMDA mutations can also result in modified synaptic plasticity (Shin et al 2020) and interference with dendritic growth (Sceniak et al 2019).…”