An Autism-Associated de novo Mutation in GluN2B Destabilizes Growing Dendrites by Promoting Retraction and Pruning

Jacob A Bahry; Karlie N Fedder-Semmes; Michael P Sceniak; Shasta L Sabo

doi:10.3389/fncel.2021.692232

An Autism-Associated de novo Mutation in GluN2B Destabilizes Growing Dendrites by Promoting Retraction and Pruning

Front Cell Neurosci. 2021 Jul 30:15:692232. doi: 10.3389/fncel.2021.692232. eCollection 2021.

Authors

Jacob A Bahry^{1

2}, Karlie N Fedder-Semmes³, Michael P Sceniak¹, Shasta L Sabo^{1

2

4}

Affiliations

¹ Department of Biology, Central Michigan University, Mount Pleasant, MI, United States.
² Graduate Program in Biochemistry, Cell and Molecular Biology, Central Michigan University, Mount Pleasant, MI, United States.
³ Department of Pharmacology, Case Western Reserve University, Cleveland, OH, United States.
⁴ Neuroscience Program, Central Michigan University, Mount Pleasant, MI, United States.

Abstract

Mutations in GRIN2B, which encodes the GluN2B subunit of NMDA receptors, lead to autism spectrum disorders (ASD), but the pathophysiological mechanisms remain unclear. Recently, we showed that a GluN2B variant that is associated with severe ASD (GluN2B^724t) impairs dendrite morphogenesis. To determine which aspects of dendrite growth are affected by GluN2B^724t, we investigated the dynamics of dendrite growth and branching in rat neocortical neurons using time-lapse imaging. GluN2B^724t expression shifted branch motility toward retraction and away from extension. GluN2B^724t and wild-type neurons formed new branches at similar rates, but mutant neurons exhibited increased pruning of dendritic branches. The observed changes in dynamics resulted in nearly complete elimination of the net expansion of arbor size and complexity that is normally observed during this developmental period. These data demonstrate that ASD-associated mutant GluN2B interferes with dendrite morphogenesis by reducing rates of outgrowth while promoting retraction and subsequent pruning. Because mutant dendrites remain motile and capable of growth, it is possible that reducing pruning or promoting dendrite stabilization could overcome dendrite arbor defects associated with GRIN2B mutations.

Keywords: GRIN2B gene; GluN2B (NMDA receptor subunit NR2B); NMDA receptor; autism; dendrite development; live imaging; neurodevelopment.