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Updated: Aug 3, 2025
Precise Brain Mapping to Perform Repetitive In Vivo Imaging of Neuro-Immune Dynamics in Mice
Published on: August 7, 2020
Dynamic changes in microglia in the mouse hippocampus during administration and withdrawal of the CSF1R inhibitor
Qirun Wang1,2, Yi-Yan Wang1,2, Wen-Jun Pu1,2
1Psychiatric Laboratory and Mental Health Center, West China Hospital, Sichuan University, Chengdu, China.
Abstract:
Pexidartinib (PLX3397), a colony-stimulating factor-1 receptor (CSF1R) inhibitor, is currently in phase 1-3 clinical trials as a treatment for a variety of tumours. CSF1R signalling regulates the development, survival and maintenance of microglia, the resident brain innate immune cells. In this study, we examined the effects of PLX3397 in the drinking water of mice on microglia in the hippocampus using ionized calcium-binding adapter molecule 1 (Iba1, a microglial marker) immunocytochemistry. A high concentration of PLX3397 (1 mg/mL) significantly decreased the density of Iba1-immunoreactive cells after 7 days of exposure, but a low concentration of PLX3397 (0.5 mg/mL) did not. In addition, both low and high concentrations of PLX3397 significantly increased the intersection number, total length and maximum length of microglial processes in male mice. PLX3397 administered for 21 days eliminated microglia with 78% efficiency in males and 84% efficiency in females. Significant increases in microglial processes were found after both seven and 21 days of PLX3397 exposure in males, whereas decreases in microglial processes were observed after both 14 and 21 days of exposure in females. After PLX3397 withdrawal following its administration for 14 days in males, the soma size quickly returned to normal levels within a week. However, the microglial density, intersection number and total length of microglial processes after 3 days of recovery stabilized to untreated levels. In summary, these findings provide detailed insight into the dynamic changes in microglial number and morphology in the hippocampus in a dose- and time-dependent manner after PLX3397 treatment and withdrawal.
Insights
Pexidartinib (PLX3397) affects microglia in the brain. High doses reduce microglial density, while both doses alter microglial processes, with effects varying by sex and duration.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Colony-stimulating factor-1 receptor (CSF1R) signaling is crucial for microglia, the brain's immune cells.
- Pexidartinib (PLX3397) is a CSF1R inhibitor investigated for cancer treatment.
- Understanding PLX3397's impact on microglia is essential for its therapeutic applications.
Purpose of the Study:
- To investigate the effects of Pexidartinib (PLX3397) on hippocampal microglia in mice.
- To determine dose- and time-dependent changes in microglial density and morphology.
- To assess the reversibility of PLX3397's effects after drug withdrawal.
Main Methods:
- Mice received Pexidartinib (PLX3397) in drinking water at varying concentrations (0.5 and 1 mg/mL) and durations (7, 14, and 21 days).
- Microglia were analyzed using ionized calcium-binding adapter molecule 1 (Iba1) immunocytochemistry.
- Morphological parameters, including cell density and process characteristics, were quantified.
Main Results:
- A high concentration (1 mg/mL) of PLX3397 significantly reduced microglial density after 7 days.
- Both low and high concentrations increased microglial process complexity in male mice.
- PLX3397 treatment for 21 days eliminated a significant percentage of microglia (78% in males, 84% in females).
- Sex-specific differences in microglial process changes were observed.
- Effects on microglial density and morphology were largely reversible after drug withdrawal.
Conclusions:
- Pexidartinib (PLX3397) administration leads to dose- and time-dependent alterations in microglial number and morphology in the hippocampus.
- The drug's effects on microglia are sex-dependent and reversible upon cessation of treatment.
- These findings provide critical insights into the neuro-immune modulating potential of CSF1R inhibitors.
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