Systematic characterization of subchronic MK-801 administration across mouse strains identifies conserved synaptic alterations and a clear cognitive phenotype in C57BL/6J mice.

BACKGROUND: The N-methyl-d-aspartate (NMDA) receptor hypofunction hypothesis is central to schizophrenia, yet pharmacological MK-801 models exhibit variability across strains and conditions. We systematically compared behavioral and synaptic phenotypes induced by subchronic MK-801 administration across commonly used mouse strains and characterized associated transcriptomic alterations in C57BL/6J mice. METHODS: Subchronic MK-801 administration during early adulthood was compared across C57BL/6J, ddY, and ICR strains under matched conditions. Recognition memory and medial prefrontal cortical dendritic spine density were assessed. Bulk and single-cell RNA sequencing were performed in C57BL/6 J mice following a drug-free washout period. RESULTS: MK-801 induced a directionally consistent reduction in dendritic spine density across all strains, reaching statistical significance in C57BL/6J and ddY mice. In contrast, a clear recognition memory impairment in the novel object recognition test was reliably detected only in C57BL/6J mice. Based on these combined phenotypes, C57BL/6J mice were selected for molecular profiling. Bulk RNA sequencing revealed persistent downregulation of synapse-related pathways alongside altered metabolic and translational programs. Single-cell RNA sequencing suggested exploratory transcriptional modulation within microglial states without major changes in overall cell-type composition. CONCLUSIONS: Subchronic MK-801 administration produces directionally consistent synaptic alterations across strains and a reliable cognitive phenotype in C57BL/6J mice. These findings provide a practical and tractable framework for selecting and interpreting pharmacological MK-801 models in preclinical schizophrenia research.