Grin2a Hypofunction Impairs Spatial Working Memory and Disrupts Hippocampal Network Oscillations and Excitatory-Inhibitory Balance.

BACKGROUND: NMDA receptors, particularly those containing the GluN2A subunit, are critical for hippocampal-dependent learning and memory. The GluN2A subunit is encoded by the GRIN2A gene and is essential for maintaining cognitive function, including working memory. In this study, we explored how full or partial ablation of the mouse Grin2a gene impairs working memory and disrupts hippocampal network oscillations and excitatory/inhibitory (E/I) balance. METHODS: Male Grin2a mutant mice were assessed for spatial working memory deficits using the 8-arm radial maze. We utilized multielectrode arrays and whole-cell patch-clamp electrophysiology to evaluate network oscillations and synaptic inputs to pyramidal cells in ex vivo hippocampal slices. We performed an immunohistochemical analysis of hippocampal slices to evaluate changes in the abundance of GABAergic (gamma-aminobutyric acidergic) neurons. RESULTS: Grin2a deficiency impaired spatial working memory and disrupted coupling of theta-gamma oscillations in the hippocampus. Moreover, Grin2a mutants expressed an overabundance of parvalbumin-expressing interneurons that integrated into hippocampal circuits and destabilized E/I input to CA1 pyramidal neurons. CONCLUSIONS: This study highlights the critical role of GluN2A-containing NMDA receptors in maintaining hippocampal network synchrony. Impairments in network synchrony and E/I balance within the hippocampus may contribute to cognitive deficits observed in Grin2a-related disorders such as schizophrenia, epilepsy, and intellectual disability.