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Microglial depletion exacerbates axonal damage and motor dysfunction in mice with cuprizone-induced demyelination
Shinji Yamamoto1, Kensuke Iwasa2, Anzu Yamagishi1
1Department of Pharmacology, Faculty of Medicine, Saitama Medical University, 38 Moro-hongo, Moroyama-machi, Iruma-gun, Saitama 350-0495, Japan; School of Medical Technology, Faculty of Health and Medical Care, Saitama Medical University, 1397-1 Yamane, Hidaka-shi, Saitama 350-1241, Japan.
Abstract:
The cuprizone (CPZ)-induced demyelination model, an animal model of Multiple sclerosis (MS), is characterized by demyelination and motor dysfunction due to microglial-mediated neuroinflammation. To determine the contribution of microglia to motor function during CPZ-induced demyelination, the microglia of mice in the CPZ-model were depleted using PLX3397 (PLX), an orally bioavailable selective colony stimulating factor 1 receptor inhibitor. PLX treatment aggravated motor dysfunction as shown by the pole, beam walk, ladder walk, and rotarod tests. PLX treatment removed microglia from the superior cerebellar peduncle (SCP), but not from the corpus callosum (CC). Although PLX treatment did not affect the degree of demyelination in both of CC and SCP, the expression of axonal damage marker APP (amyloid precursor protein) was increased. Increased TNF-α, IL-1β, and iNOS expressions were observed in PLX-treated mice. These results suggest that microglial depletion exacerbates axonal damage and motor dysfunction in CPZ model mice. In this study, we found that microglia contribute to motor function and axon-protective effects in CPZ-induced demyelination.
Insights
Microglia depletion worsened motor deficits and axonal damage in a mouse model of Multiple Sclerosis (MS). These findings highlight microglia
Area of Science:
- Neuroscience
- Immunology
- Pathology
Background:
- Multiple Sclerosis (MS) is a demyelinating disease characterized by neuroinflammation.
- Microglia are implicated in MS pathogenesis, but their precise role in motor function during demyelination is unclear.
- The cuprizone (CPZ) mouse model mimics MS, inducing demyelination and motor deficits.
Purpose of the Study:
- To investigate the contribution of microglia to motor function in the CPZ-induced demyelination model.
- To assess the impact of microglial depletion on neuroinflammation and axonal integrity.
Main Methods:
- Mice were treated with cuprizone (CPZ) to induce demyelination.
- Microglia were depleted using PLX3397 (PLX), a CSF1R inhibitor.
- Motor function was evaluated using pole, beam walk, ladder walk, and rotarod tests.
- Demyelination, microglial distribution, axonal damage (APP), and inflammatory markers (TNF-α, IL-1β, iNOS) were assessed.
Main Results:
- PLX3397 treatment exacerbated motor dysfunction in CPZ-treated mice.
- Microglial depletion occurred in the superior cerebellar peduncle (SCP) but not the corpus callosum (CC).
- Axonal damage marker APP expression increased, while demyelination levels remained unchanged.
- Pro-inflammatory markers TNF-α, IL-1β, and iNOS were upregulated following microglial depletion.
Conclusions:
- Microglial depletion worsens axonal damage and motor dysfunction in the CPZ model.
- Microglia play a crucial role in maintaining motor function and providing axon protection during demyelination.
- Targeting microglia requires careful consideration due to their protective functions in MS models.
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