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Autism spectrum disorders (ASDs) are four times more common in males than in females, but the underlying mechanisms are poorly understood. We characterized sexually dimorphic changes in mice carrying a heterozygous mutation in Chd8 (Chd8+/N2373K) that was first identified in human CHD8 (Asn2373LysfsX2), a strong ASD-risk gene that encodes a chromatin remodeler. Notably, although male mutant mice displayed a range of abnormal behaviors during pup, juvenile, and adult stages, including enhanced mother-seeking ultrasonic vocalization, enhanced attachment to reunited mothers, and isolation-induced self-grooming, their female counterparts do not. This behavioral divergence was associated with sexually dimorphic changes in neuronal activity, synaptic transmission, and transcriptomic profiles. Specifically, female mice displayed suppressed baseline neuronal excitation, enhanced inhibitory synaptic transmission and neuronal firing, and increased expression of genes associated with extracellular vesicles and the extracellular matrix. Our results suggest that a human CHD8 mutation leads to sexually dimorphic changes ranging from transcription to behavior in mice.

Original publication

DOI

10.1038/s41593-018-0208-z

Type

Journal article

Journal

Nat Neurosci

Publication Date

09/2018

Volume

21

Pages

1218 - 1228

Keywords

Animals, Anxiety, Separation, Behavior, Animal, DNA-Binding Proteins, Extracellular Matrix, Female, Gene Expression, Hippocampus, Male, Mice, Mice, Inbred C57BL, Neurons, Object Attachment, Sex Characteristics, Signal Transduction, Social Behavior, Synaptic Transmission, Transcriptome, Vocalization, Animal