Effects of NMDA receptor antagonists on working memory and gamma oscillations, and the mediating role of the GluN2D subunit.
Chitra Vinnakota, Matthew R Hudson, Kazutaka Ikeda, Soichiro Ide, Masayoshi Mishina, Suresh Sundram, Nigel C Jones, Rachel Anne Hill
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology May 15, 2025 DOI: 10.1038/s41386-025-02129-9 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study with knockout mice and pharmacological challenge Peer reviewed |
|---|---|
| Population | Wildtype and GluN2D-knockout mice |
| Interventions | (S)-ketamine (R)-ketamine MK-801 saline |
| Dose | 30 mg/kg (S)-ketamine, 30 mg/kg (R)-ketamine, 1 mg/kg PCP, 0.3 mg/kg MK-801 |
| Keywords | Cognitive function Brain waves Memory research Neural receptors |
| Citations | 6 |
| Key findings | PCP disrupts working memory and increases hippocampal gamma power via the GluN2D subunit, while task-induced low gamma activity during memory maintenance is disrupted by all NMDA receptor antagonists. |
Abstract
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.