Enhanced stability of hippocampal place representation caused by reduced magnesium block of NMDA receptors in the dentate gyrus

Background: Voltage-dependent block of the NMDA receptor by Mg²⁺ is thought to be central to the unique involvement of this receptor in higher brain functions. However, the in vivo role of the Mg²⁺ block in the mammalian brain has not yet been investigated, because brain-wide loss of the Mg²⁺ block causes perinatal lethality. In this study, we used a brain-region specific knock-in mouse expressing an NMDA receptor that is defective for the Mg²⁺ block in order to test its role in neural information processing. Results: We devised a method to induce a single amino acid substitution (N595Q) in the GluN2A subunit of the NMDA receptor, specifically in the hippocampal dentate gyrus in mice. This mutation reduced the Mg²⁺ block at the medial perforant path-granule cell synapse and facilitated synaptic potentiation induced by high-frequency stimulation. The mutants had more stable hippocampal place fields in the CA1 than the controls did, and place representation showed lower sensitivity to visual differences. In addition, behavioral tests revealed that the mutants had a spatial working memory deficit. Conclusions: These results suggest that the Mg²⁺ block in the dentate gyrus regulates hippocampal spatial information processing by attenuating activity-dependent synaptic potentiation in the dentate gyrus.