Synaptic plasticity involves changes in cytoskeleton proteins and postsynaptic receptors including NMDA receptors (NMDAR). These receptors are heterotetramers composed by two obligatory (GluN1) and two regulatory subunits, being GluN2A and GluN2B the most expressed in cognitive related brain structures. In the last years, grin2A mutations were associated with complex phenotypes that led to neurodevelopmental disorders which include the occurrence of seizures and in some cases, decreased GluN2A levels. In order to better understand the role of GluN2A reduced expression in synaptic plasticity and behavior, we induced a GluN2A knock-down (GluN2A-KD) in two models: primary mature hippocampal neuronal cultures and in the CA1 hippocampal region of young adult Wistar rats. In vivo, the GluN2A KD animals showed increased seizure susceptibility, induced after PTZ injection. Furthermore, in vitro, the GluN2A-KD neurons showed higher glutamate sensibility than control ones in calcium imaging assays, as well as, changes in dendritic branching and synapse number which were observed by immunofluorescence. Altogether, these results suggest that GluN2A down regulation, alter glutamate responsiveness and would facilitate seizure outcome that is a hallmark in patients carrying grin2A mutations.