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MK-801 neurotoxicity in male mice: histologic effects and chronic impairment in spatial learning
D F Wozniak1, G Brosnan-Watters, A Nardi
1Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA.
Abstract:
Several histological and behavioral experiments were conducted to investigate the neurotoxic effects of MK-801 in male mice. Moderate subcutaneous (s.c.) doses of MK-801 (0.5 and 1.0 mg/kg) induced the formation of intracytoplasmic vacuoles in pyramidal neurons in layers III and IV of the posterior cingulate/retrosplenial (PC/RS) cortex in 50% and 100% of the mice from the two respective treatment groups. Electron microscopic analysis of the vacuoles indicated that mitochondria and endoplasmic reticulum are the cellular organelles most prominently involved in this pathomorphological change. Treating mice with a high systemic dose of MK-801 (10 mg/kg s.c. or intraperitoneal (i.p.)) caused selective, irreversible degeneration of a small number of PC/RS cortical neurons. Compared to saline controls, the acquisition performance of mice treated i.p. with 10 mg/kg MK-801 was chronically impaired on a spatial learning task (modified hole board food search task) when tested at several posttreatment intervals (up to at least 5 months), although the groups did not differ on activity or sensorimotor tests conducted 2 weeks posttreatment. In summary, MK-801 caused histopathological changes in the mouse brain similar to those observed in the rat. Furthermore, high dose MK-801 treatment that killed a small number of mouse PC/RS cortical neurons resulted in a chronic acquisition impairment in spatial learning, an effect not previously demonstrated in any species.
Insights
MK-801 causes brain cell damage and chronic spatial learning deficits in mice. This neurotoxicity, particularly in the posterior cingulate/retrosplenial cortex, impacts learning and memory.
Area of Science:
- Neuroscience
- Toxicology
- Cell Biology
Background:
- MK-801 is an NMDA receptor antagonist.
- Its neurotoxic effects require further investigation.
Purpose of the Study:
- To investigate the neurotoxic effects of MK-801 in male mice.
- To examine histopathological and behavioral changes following MK-801 administration.
Main Methods:
- Mice were administered MK-801 via subcutaneous (s.c.) or intraperitoneal (i.p.) injection at varying doses.
- Histological and electron microscopic analyses were performed on brain tissue.
- Behavioral testing assessed spatial learning, activity, and sensorimotor function.
Main Results:
- Moderate MK-801 doses induced intracytoplasmic vacuoles in PC/RS cortical neurons, involving mitochondria and endoplasmic reticulum.
- High MK-801 doses caused selective, irreversible neuronal degeneration in the PC/RS cortex.
- Mice treated with high-dose MK-801 exhibited chronic impairment in spatial learning acquisition.
Conclusions:
- MK-801 induces dose-dependent histopathological changes in the mouse brain.
- High-dose MK-801 causes chronic spatial learning deficits linked to neuronal degeneration.
- These findings demonstrate a novel link between MK-801-induced neurodegeneration and impaired spatial learning.
