Effects of NMDA receptor antagonists on working memory and gamma oscillations, and the mediating role of the GluN2D subunit

Working memory relies on synchronised network oscillations involving complex interplay between pyramidal cells and GABAergic interneurons. NMDA receptor (NMDAR) antagonists influence both network oscillations and working memory, but the relationship between these two consequences has not been elucidated. This study aimed to determine the effect of NMDAR antagonists on network oscillations during a working memory task in mice, and the contribution of the GluN2D receptor subunit. After training wildtype (WT) and GluN2D-knockout (KO) mice on the Trial-Unique-Non-match to Location (TUNL) touchscreen task of working memory, recording electrodes were implanted into the prefrontal cortex (PFC) and hippocampus. Mice were challenged with either (S)-ketamine (30 mg/kg), (R)-ketamine (30 mg/kg), phencyclidine (PCP, 1 mg/kg), MK-801 (0.3 mg/kg) or saline prior to TUNL testing while simultaneous local field potential recordings were acquired. PCP disrupted working memory accuracy in WT (p = 0.001) but not GluN2D-KO mice (p = 0.79). MK-801 (p < 0.0001), (S)-ketamine (p < 0.0001) and (R)-ketamine (p = 0.007) disrupted working memory accuracy in both genotypes. PCP increased baseline hippocampal gamma (30-80 Hz) power in WT (p = 0.0015) but not GluN2D-KO mice (p = 0.92). All drugs increased baseline gamma power in the PFC in both genotypes (p < 0.05). Low gamma was induced during the maintenance phase of the TUNL task and increased when mice correctly completed the task (p = 0.024). This response-dependent increase in low gamma was disrupted by all drugs. In summary, PCP action involves the GluN2D subunit of the NMDA receptor in the hippocampus to alter baseline gamma power and working memory. Task-induced low gamma activity during maintenance aligns with task performance, and is disrupted by all NMDAR antagonists.