Reactive astrogliosis induced by neuronal GluN2A knockdown

Alterations in the expression or localization of NMDA receptors (NMDARs) are associated with multiple neuropathologies. NMDARs are tetramers composed of two GluN1 subunits and two regulatory subunits. In the mature brain, the predominant regulatory subunit is GluN2A. However, mutations in the GRIN2A gene lead to decreased GluN2A expression, resulting in complex phenotypes ranging from neurodevelopmental disorders and intellectual disability to schizophrenia. In our laboratory, we developed a GluN2A knockdown (GluN2A-kd) model in adult rats to investigate the consequences of reduced GluN2A expression. In this model, we found that GluN2A-kd neurons exhibit a more excitable phenotype both in vitro and in vivo. As increased neuronal excitability is often associated with enhanced astrocyte reactivity, we examined astrocyte morphology and reactivity. In this work, we found that GluN2A-kd induced increased astrocyte reactivity in vitro, as evidenced by an increase in astrocytic area. Additionally, we observed altered levels of reactive oxygen species (ROS). These results led us to hypothesize that reduced GluN2A expression induces astrogliosis, which could be an initial cellular response contributing to the hyperexcitability observed in vitro and in vivo in our GluN2A-kd model.