Sex-Dependent and cell-type specific effects of autism associated gene CHD8 on behavior during adulthood

CHD8 was identified as one of the top autism-associated genes. Interestingly, mutations in CHD8 are found particulary in males diagnosed with autism. There are many open questions regarding the mechanisms through which CHD8 affects specifically males, which brain cell types are responsible for the behavioral phenotypes, and if CHD8 also plays a role in behavior during adulthood.

To gain insight into these questions, we created two separate mouse models with conditional deletion of CHD8 in excitatory neurons or microglia. Deletion of CHD8 was performed during adulthood to study adulthood-specific effects.

Adulthood CHD8 knockout in excitatory neurons induced an increase in freezing in contextual fear conditioning in both male and female mice. However, specifically male, and not female, CHD8 cKO mice displayed depressive-like behavior in both tail suspension and forced swim test. Interestingly, there were no differences in either sex in social behavior and anxiety behavior. RNA-seq in hippocampus determined an enhanced estrogen receptor 1 expression in both sexes compared to WT mice.

In adulthood CHD8 cKO in microglia, female cKO mice showed normal behavior in all tests, while male cKO mice had significant anxiety-like behavior in several anxiety tests (open field, dark light and elevated plus maze). In addition, male CHD8 cKO in microglia showed depression-like behavior, similar to the neuron-specific knockout. Motor tests were normal for both sexes.

We propose that CHD8 expression has unique role in adulthood in different cells. In addition, it has novel sex dependent effects in excitatory neurons and microglia.