GluN2A reduced expression induces a delay in neuron maturation involved in seizure susceptibility

BAEZ, MARÍA VERÓNICA; ACUTAIN, MARIA FLORENCIA

Congreso; ISN-ESN 2023 Meeting; 2023

International Society of Neurochemistry

NMDA receptors (NMDAR) are composed by two GluN1 and two regulatory subunits. GluN2A and GluN2B are the NMDAR most expressed regulatory subunits in cognitive related brain structures, like hippocampus, being GluN2B characteristic of immature structures and GluN2A of mature ones. This balance in GluN2-type subunits is responsible for adequate glutamatergic neurotransmission, which is altered in several pathological conditions. Both changes in GluN2A expression or mislocalization due to grin2A mutations were associated with complex phenotypes that led to neurodevelopmental disorders that include the occurrence of seizures. However, little is known about the role of GLuN2A decreased expression in these phenotypes. In order to better understand the role of GluN2A reduction in synaptic plasticity and behavior, we induced a knock-down (GluN2A-KD) in mature neuronal cultures. We study neuron functionality and morphology and found that GluN2A-KD neurons had increased responses to glutamate stimulus which could be attributed to an increase in immature dendritic spines and dendritic branching. Furthermore, we analyzed NMDAR subcellular localization and observed that while NMDAR total levels measured by GLuN1 total subunit are decreased, surface GluN2A levels remains similar to controls. These results suggest that the new spines are immature, hence, we study different parameters in neuron maturation from 5 to 20 DIVs. We analyzed GluN2A/GluN2B ratio, index branching and glutamate response, and discovered that GluN2A-KD neurons showed a delay in neuron maturation which would be the cause, in vivo, of seizure susceptibility.