Sexually dimorphic behavior, neuronal activity, and gene expression in Chd8-mutant mice

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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.
Publisher
NATURE PUBLISHING GROUP
Issue Date
2018-09
Language
English
Article Type
Article
Keywords

AUTISM SPECTRUM DISORDER; SOCIAL-INTERACTION; MOUSE MODELS; CHD8; MUTATIONS; LACKING; ATLAS; ABNORMALITIES; CONNECTIVITY; ARCHITECTURE

Citation

NATURE NEUROSCIENCE, v.21, no.9

ISSN
1097-6256
DOI
10.1038/s41593-018-0208-z
URI
http://hdl.handle.net/10203/245906
Appears in Collection
BiS-Journal Papers(저널논문)BS-Journal Papers(저널논문)
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