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

Hwajin Jung, Haram Park, Yeonsoo Choi, Hyojin Kang, Eunee Lee, Hanseul Kweon, Junyeop Daniel Roh, Jacob Ellegood, Woochul Choi, Jaeseung Kang, Issac Rhim, Su Yeon Choi, Mihyun Bae, Sun Gyun Kim, Jiseok Lee, Changuk Chung, Taesun Yoo, Hanwool Park, Yangsik Kim, Seungmin HaSeung Min Um, Seojung Mo, Yonghan Kwon, Won Mah, Yong Chul Bae, Hyun Kim, Jason P. Lerch, Se Bum Paik, Eunjoon Kim

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24 Citations (Scopus)

Abstract

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 languageEnglish
Pages (from-to)1218-1228
Number of pages11
JournalNature Neuroscience
Volume21
Issue number9
DOIs
Publication statusPublished - 2018 Sep 1

ASJC Scopus subject areas

  • Neuroscience(all)

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    Jung, H., Park, H., Choi, Y., Kang, H., Lee, E., Kweon, H., Roh, J. D., Ellegood, J., Choi, W., Kang, J., Rhim, I., Choi, S. Y., Bae, M., Kim, S. G., Lee, J., Chung, C., Yoo, T., Park, H., Kim, Y., ... Kim, E. (2018). Sexually dimorphic behavior, neuronal activity, and gene expression in Chd8-mutant mice. Nature Neuroscience, 21(9), 1218-1228. https://doi.org/10.1038/s41593-018-0208-z