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

Authors

Fumiko Yoshimachi, Minori Ikuta, Karina Kimura, Hongbo Wang, Jinghang Fu, Hinako Kirikae, Anusree Kumar, Yasuyuki Shima, Yui Yamamoto, Hirofumi Miyazaki, Mai Sakai, Zhiqian Yu, Hiroaki Tomita, Yuji Owada, Motoko Maekawa

Published in

Progress in neuro-psychopharmacology & biological psychiatry. Pages 111921. Sep 08, 2026. Epub Sep 08, 2026.

Abstract

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.
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.
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.
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.

PMID:
42710731
Bibliographic data and abstract were imported from PubMed on 09 Sep 2026.

Read full publication at:
Please sign in to see all details.

Stats

1-terrible, 9-excellent. How would you rate this publication? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.