GluN2D-containing NMDA receptors regulate dentate gyrus function by facilitating granule cell activity and mediating synaptic plasticity

N-Methyl-D-aspartate ionotropic glutamate receptors (NMDARs) are crucial for synaptic transmission, long-term plasticity, neuronal activity, and cognition. Consistent with these functions, NMDAR dysfunction is linked to several brain disorders, including Alzheimers disease, autism, schizophrenia, and depression. NMDARs are tetrameric complexes composed of two essential GluN1 subunits and two distinct GluN2 subunits (GluN2A-D) that define their functional characteristics. Although the roles of GluN2A and GluN2B, which are highly expressed in the brain, have been extensively studied, much less is known about GluN2D in brain function. Using selective GluN2D antagonists in the mature rodent brain and a conditional GluN2D knockout model, we assessed the role of GluN2D-containing NMDARs in dentate granule cells. We found these receptors are tonically active, mainly extrasynaptic, and promote granule cell action-potential firing. Additionally, physiologically relevant presynaptic and postsynaptic activity patterns induced strong long-term potentiation of NMDAR-mediated transmission at medial perforant path synaptic inputs, and this plasticity was driven by GluN2D lateral diffusion and facilitated by non-canonical glutamate delta-1 (GluD1) receptors. Finally, removing GluN2D from granule cells impaired spatial memory. Overall, our findings demonstrate that GluN2D-containing NMDARs are vital for hippocampal function by modulating granule cell activity and supporting synaptic plasticity.