Cellular and Molecular Neurobiology
Author: Maria Florencia Acutain | Email: facutain@yahoo.com
Maria Florencia Acutain1°, Maria Verónica Baez1°2°
1° Instituto de Biología Celular y Neurociencia (IBCN). CONICET-UBA
2° Facultad de Medicina – UBA
NMDA receptors (NMDARs) are composed of two obligatory GluN1 subunits and two regulatory subunits encoded by grin genes. In the brain, the most commonly expressed regulatory subunits are GluN2A and GluN2B, which are tightly regulated both temporally and spatially. Mutations in the grin2A gene are associated with complex phenotypes, that could include reduced expression of GluN2A. In our last work, we induced a GluN2A knock-down (GluN2A-KD) in mature hippocampal neuronal cultures, which led to a more immature phenotype and a reduced GluN2A/GluN2B ratio compared to control neurons.
In the current study, we further investigated GluN2A-KD by analyzing GluN1 expression and its subcellular localization. We observed that GluN2A-KD led to a decrease in GluN1 protein levels, which was reflected in reduced NMDAR levels at the synaptic sites. However, dendritic GluN1 clusters remained unaffected in GluN2A-KD neurons. Additionally, we noted a shift in GluN1 splicing variants favoring those associated with forward trafficking. These findings suggest that GluN2A down-regulation alters synaptic NMDAR levels by modifying GluN1 expression through changes in splicing variant balance. We hypothesize that this rearrangement contributes to the observed phenotype in the GluN2A-KD cultured neurons. Further experiments are needed to validate this hypothesis.