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An Autism-Associated de novo Mutation in GluN2B Destabilizes Growing Dendrites by Promoting Retraction and Pruning
Jacob A Bahry1,2, Karlie N Fedder-Semmes3, Michael P Sceniak1
1Department of Biology, Central Michigan University, Mount Pleasant, MI, United States.
Frontiers in Cellular Neuroscience
|August 16, 2021
Summary
Mutations in GRIN2B genes cause autism spectrum disorder (ASD) by impairing neuron dendrite growth. This study reveals that a specific GRIN2B variant disrupts dendrite development by increasing retraction and pruning, hindering brain complexity.
Area of Science:
- Neuroscience
- Genetics
- Developmental Biology
Background:
- Mutations in GRIN2B, encoding the GluN2B subunit of NMDA receptors, are linked to autism spectrum disorders (ASD).
- Previous research indicated that a severe ASD-associated GRIN2B variant (GluN2B724t) impairs dendrite morphogenesis, but the precise mechanisms were unclear.
Purpose of the Study:
- To investigate the specific effects of the GluN2B724t variant on the dynamics of dendrite growth and branching in developing neurons.
- To elucidate the pathophysiological mechanisms underlying GRIN2B-associated ASD related to neuronal structure.
Main Methods:
- Utilized time-lapse imaging to observe dendrite growth dynamics in rat neocortical neurons expressing either wild-type or GluN2B724t.
- Quantified branch extension, retraction, and pruning rates to analyze changes in dendrite morphogenesis.
Main Results:
- Expression of GluN2B724t shifted neuronal branch motility from extension towards retraction.
- While new branch formation rates were similar between mutant and wild-type neurons, mutant neurons showed significantly increased dendritic branch pruning.
- These dynamic alterations led to a near-complete absence of the normal net expansion in arbor size and complexity.
Conclusions:
- ASD-associated GRIN2B mutations disrupt dendrite morphogenesis by reducing outgrowth and increasing retraction and pruning, ultimately impairing neuronal arbor development.
- The findings suggest that therapeutic strategies aimed at reducing pruning or enhancing dendrite stabilization may offer potential interventions for GRIN2B-related ASD phenotypes.
