Reduced GluN2A expression recapitulates schizophrenia relevant behavioral and synaptic features

NMDA receptors (NMDAR) play a crucial role in synaptic plasticity during development and adulthood. Alterations in the expression of one of the regulatory subunits, GluN2A, have been linked to phenotypes that contribute to neurodevelopmental disorders or to schizophrenia (SCZ). GluN2A expression rise during postnatal development both in human and rodents. As SCZ was proposed to present NMDAR hypofunction, GluN2A downregulation emerges as a possible mechanism involved in disease onset. However, the role of altered GluN2A remains poorly understood. For this reason, we established a GluN2A knockdown (GluN2A-KD) model in young adult rats. Behavioral analyses revealed impairments in spatial map formation, reduced cognitive flexibility, and altered exploration patterns, while general cognition remained intact. To better understand the molecular mechanisms behind these phenomena, we characterize the GluN2A-KD in neuronal cultures. Despite reduced GluN2A expression, synaptic GluN2A levels remain similar to controls. Moreover, we observed an increase in dendritic branching and immature dendritic spines, associated with an increase in glutamate responsiveness. These findings suggest that GluN2A-kd promotes immature neuronal morphology and excitatory imbalance, consistent with the glutamate hypothesis of SCZ. More experiments are required to clarify the molecular mechanisms underlying glutamate sensitivity, as well as the molecular dysregulation consequence of GluN2A-kd.