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Updated: Aug 4, 2026
Assessment of Sexual Behavior of Male Mice
Published on: March 5, 2020
CHD8 adulthood microglial knockdown in C57BL6 mice induces behavioral, morphological, and transcriptional changes in
Orly Weissberg1, Ram Harari1, Chizim Dogun1
1Azrieli Faculty of Medicine, Bar Ilan University, Safed, Israel.
Abstract:
Mutations in CHD8 (chromodomain-helicase-DNA binding protein 8) are highly associated with autism spectrum disorders. It has been well established that CHD8 has a prominent role in the development of neurons. However, there is little knowledge of its specific roles in microglia, and its possible roles in cellular functions after development, i.e. adulthood. In addition, while microglial dysfunction has been characterized in autism, the roles of autism-associated genes in microglial function have not been well characterized. Using conditional knockdown technology in C57BL6 mice models, we determined that adulthood deletion of Chd8 in microglia induces robust changes in behavior, including anxiety, social deficits, and depression-like behavior, in association with changes in microglial activation and robust microglial gene expression changes in the whole brain, including expression of cytokines. Of great interest, many of these changes were seen specifically in male deletion mice, and not female deletion mice. In contrast, adulthood neuron knockdown had more subtle effects on behavior, mainly on depression-like behavior in males. In addition, neuronal knockdown leads to upregulation of genes associated with Hedgehog and Wnt/Beta-catenin pathways in the hippocampus specifically in males. In summary, CHD8 is particularly important for microglial function in adulthood and has cellular effects that are specific to males in C57BL6 mice.
Insights
Chromodomain-helicase-DNA binding protein 8 (CHD8) is crucial for adult microglial function. Its deletion in mice causes behavioral changes, particularly in males, highlighting sex-specific roles in autism spectrum disorder.
Area of Science:
- Neuroscience
- Genetics
- Cell Biology
Background:
- Mutations in CHD8 are linked to autism spectrum disorders (ASD).
- CHD8 is known for its role in neuronal development, but its function in adult microglia is poorly understood.
- Microglial dysfunction is implicated in ASD, yet the role of ASD-associated genes in microglial function remains unclear.
Purpose of the Study:
- To investigate the role of CHD8 in adult microglial function.
- To examine the behavioral and molecular consequences of adult microglial CHD8 deletion.
- To explore potential sex-specific effects of CHD8 deletion in microglia and neurons.
Main Methods:
- Conditional knockdown of Chd8 in microglia and neurons of adult C57BL6 mice.
- Behavioral testing to assess anxiety, social interaction, and depression-like behaviors.
- Whole-brain gene expression analysis, including cytokine profiling.
- Hippocampal gene expression analysis focusing on specific signaling pathways.
Main Results:
- Adult microglial Chd8 deletion induced significant behavioral changes (anxiety, social deficits, depression-like behavior) in mice.
- These behavioral changes were associated with altered microglial activation and gene expression, including cytokines.
- Many observed effects were specific to male mice, with less pronounced effects in females.
- Neuronal Chd8 knockdown had subtler behavioral effects, primarily depression-like behavior in males.
- Neuronal knockdown led to upregulation of Hedgehog and Wnt/Beta-catenin pathway genes in the male hippocampus.
Conclusions:
- CHD8 plays a critical role in maintaining adult microglial function.
- Adult microglial CHD8 deficiency leads to behavioral deficits and molecular alterations, with notable sex-specific differences.
- These findings suggest CHD8's importance in microglial biology relevant to ASD, particularly in males.
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