Age-differential sexual dimorphisms in CHD8-S62X-mutant mouse synapses and transcriptomes

Area of Science:

• Neuroscience
• Genetics
• Developmental Biology

Background:

• The chromodomain helicase DNA binding protein 8 (Chd8) is a crucial regulator of gene expression implicated in neurodevelopmental disorders.
• Mutations in CHD8 are associated with autism spectrum disorder (ASD) and other neurodevelopmental conditions.
• Understanding the precise role of Chd8 in brain development and behavior is essential for deciphering ASD pathogenesis.

Purpose of the Study:

• To investigate the behavioral, synaptic, and transcriptomic consequences of distinct Chd8 mutations in mice.
• To examine age- and sex-dependent effects of Chd8 dysfunction.
• To elucidate the sexually dimorphic nature of Chd8-related neurodevelopmental alterations.

Main Methods:

• Utilized two mouse models with different Chd8 truncating mutations (N2373K and S62X).
• Assessed autistic-like behaviors through standardized behavioral tests.
• Performed electrophysiological recordings to analyze excitatory synaptic transmission.
• Conducted transcriptomic analysis to identify gene expression changes.

Main Results:

• Chd8 mutations induced autistic-like behaviors with distinct patterns in males and females, varying by age and mutation type.
• Excitatory synaptic transmission showed suppressed or enhanced function depending on age, sex, and mutation.
• Transcriptomic profiles revealed age- and sex-specific alterations in gene expression related to ASD.
• Significant age-differential sexual dimorphisms were observed across behavioral, synaptic, and transcriptomic levels.

Conclusions:

• Chd8 mutations lead to complex, age- and sex-specific neurobiological changes relevant to autism spectrum disorder.
• The study underscores the critical role of Chd8 in sexually dimorphic brain development.
• These findings provide insights into the heterogeneous nature of ASD and potential therapeutic targets.