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

Nature Neuroscience volume 21, pages 1218–1228 (2018)Cite this article

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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.

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Fig. 1: Chd8+/N2373K mice display male-preponderant autistic-like behaviors.
Fig. 2: Distinct c-fos signals in male and female Chd8+/N2373K brains under baseline and maternal-separation conditions.
Fig. 3: Opposite changes in inhibitory synaptic transmission in the hippocampus of male and female Chd8+/N2373K mice.
Fig. 4: Opposite changes in excitatory and inhibitory neuronal firing in the hippocampus of male and female Chd8+/N2373K mice.
Fig. 5: Distinct transcriptomic patterns in male and female Chd8+/N2373K mice revealed by DEG analyses.
Fig. 6: Distinct enrichments of genes from male and female Chd8+/N2373K mice for ASD-related and cell-type-specific gene sets, as revealed by GSEA.

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Acknowledgements

This work was supported by the NRF Grant 2013M3C7A1056732 (to H.K.), the Future Systems Healthcare Project of KAIST (to S.P.), KISTI K-16-L03-C02-S01 (to H. Kang), and the Institute for Basic Science (IBS-R002-D1 to E.K.).

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  1. These authors contributed equally: Hwajin Jung, Haram Park.

Authors and Affiliations

  1. Center for Synaptic Brain Dysfunctions, Institute for Basic Science (IBS), Daejeon, Korea

    Hwajin Jung, Eunee Lee, Issac Rhim, Su-Yeon Choi, Mihyun Bae, Sun-Gyun Kim, Jiseok Lee & Eunjoon Kim

  2. Department of Biological Sciences, Korea Advanced Institute for Science and Technology (KAIST), Daejeon, Korea

    Haram Park, Yeonsoo Choi, Hanseul Kweon, Junyeop Daniel Roh, Jaeseung Kang, Changuk Chung, Taesun Yoo, Seungmin Ha, Seung Min Um, Yonghan Kwon & Eunjoon Kim

  3. Supercomputing Center, KISTI, Daejeon, Korea

    Hyojin Kang

  4. Mouse Imaging Centre, Hospital for Sick Children, Toronto, Ontario, Canada

    Jacob Ellegood & Jason P Lerch

  5. Program of Brain and Cognitive Engineering, Department of Bio and Brain Engineering, KAIST, Daejeon, Korea

    Woochul Choi & Se-Bum Paik

  6. Graduate School of Medical Science and Engineering, KAIST, Daejeon, Korea

    Hanwool Park & Yangsik Kim

  7. Department of Anatomy and Division of Brain Korea 21, Biomedical Science, College of Medicine, Korea University, Seoul, Korea

    Seojung Mo & Hyun Kim

  8. Department of Anatomy and Neurobiology, School of Dentistry, Kyungpook National University, Daegu, Korea

    Won Mah & Yong Chul Bae

  9. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada

    Jason P Lerch

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Contributions

W.M. designed the mouse knockout strategy. S.M. conducted in situ hybridization experiments. J.E. and J.P.L. performed MRI and DTI experiments and analysis. Y.C. and H. Kweon conducted immunohistochemistry experiments. Haram Park, H.J., Y.C., J.D.R., H. Kweon., C.C., S.H., T.Y., Hanwool Park, S.U., and S.K. conducted slice electrophysiology experiments. E.L., I.Y., W.C., and J.L. performed in vivo recording experiments and analysis. H.J., Haram Park, Y.C., J.K., M.B., S.C., S.K., Y. Kim., H. Kweon, and Y. Kwon conducted mouse behavioral experiments. Haram Park, H.J., H. Kweon, and Y.C. conducted all of the other experiments. H. Kang performed RNA transcript analysis. Y.C.B., H.K., S.P., and E.K. supervised the project and wrote the manuscript.

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Correspondence to Eunjoon Kim.

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Supplementary Information

Supplementary Text and Figures

Supplementary Figures 1–21

Reporting Summary

Supplementary Table 1

Summary of MRI and DTI analysis of brains from male and female, WT and Chd8+/N2373K mice at 4 weeks.

Supplementary Table 2

Summary of c-fos expression analyses of brains from male and female, WT and Chd8+/N2373K mice at P20.

Supplementary Table 3

All RNA-Seq data from male and female, WT and Chd8+/N2373K mice at P0 and P25 and details on all HT/WT DEGs.

Supplementary Table 4

Full GO annotations for DEGs.

Supplementary Table 5

GSEA results for C5, ASD-related, cell type-specific, and IEG-related, C2, and C3 gene sets.

Supplementary Table 6

Statistical analyses.

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Jung, H., Park, H., Choi, Y. et al. Sexually dimorphic behavior, neuronal activity, and gene expression in Chd8-mutant mice. Nat Neurosci 21, 1218–1228 (2018). https://doi.org/10.1038/s41593-018-0208-z

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