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Constitutive expression of CX3CR1-BAC-Cre introduces minimal off-target effects in microglia
Fadya H Mroue-Ruiz1, Bhoomi Desai1, Madison M Garvin1
1Neuroscience Institute and the Center for Neuroinflammation and Cardiometabolic Diseases, Georgia State University, Atlanta, GA, USA.
Abstract:
CX3CR1-Cre mouse lines have produced important advancements in our understanding of microglial biology. Recent studies have demonstrated the adverse effects of tamoxifen-induced CX3CR1-Cre expression during development, which may include changes in microglial density, phenotype, and DNA damage, as well as anxiety-like behavior. However, the unintended effects of constitutive CX3CR1-BAC-Cre expression remain unexplored. Here, we characterized the effects of CX3CR1-BAC-Cre expression on microglia in CX3CR1-BAC-Cre +/- and CX3CR1-BAC-Cre-/- male and female littermates during early postnatal development and adulthood in multiple brain regions. Additionally, we performed anxiety-like behavior tests to assess changes caused by Cre expression. We found that CX3CR1-BAC-Cre expression causes subtle region-and sex-specific changes in microglial density, volume, and morphology during development, but these changes normalized by adulthood in all brain regions except the hippocampus. No behavioral changes were identified. Our findings suggest that the constitutive-Cre model is less detrimental than the inducible model, and highlight the need for proper controls.
Insights
Constitutive CX3CR1-BAC-Cre expression in mice causes minor, temporary changes in microglia during development. This model appears less detrimental than inducible Cre systems, suggesting careful consideration of controls in microglial research.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- CX3CR1-Cre mouse models are crucial for studying microglia, the brain's immune cells.
- Tamoxifen-induced CX3CR1-Cre expression has known developmental side effects.
- The impact of constitutive CX3CR1-BAC-Cre expression on microglia is largely unknown.
Purpose of the Study:
- To investigate the effects of constitutive CX3CR1-BAC-Cre expression on microglial characteristics.
- To assess potential behavioral changes associated with CX3CR1-BAC-Cre expression.
- To compare the impact of constitutive vs. inducible CX3CR1-Cre models.
Main Methods:
- Characterization of microglia (density, volume, morphology) in CX3CR1-BAC-Cre+/- and -/- mice across brain regions and ages.
- Assessment of anxiety-like behaviors.
- Comparison between constitutive and inducible Cre models.
Main Results:
- CX3CR1-BAC-Cre expression induced subtle, region- and sex-specific microglial changes during development.
- These microglial alterations normalized by adulthood, except in the hippocampus.
- No significant anxiety-like behaviors were observed in the mice.
Conclusions:
- Constitutive CX3CR1-BAC-Cre expression has a less detrimental impact on microglia compared to inducible systems.
- The findings underscore the importance of appropriate controls in Cre-driver mouse studies.
- This model offers a potentially safer alternative for microglial research, with specific attention to hippocampal development.
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