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 Ha; Seung Min Um; Seojung Mo; Yonghan Kwon; Won Mah; Yong Chul Bae; Hyun Kim; Jason P. Lerch; Se Bum Paik; Eunjoon Kim

doi:10.1038/s41593-018-0208-z

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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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 language	English
Pages (from-to)	1218-1228
Number of pages	11
Journal	Nature Neuroscience
Volume	21
Issue number	9
DOIs	https://doi.org/10.1038/s41593-018-0208-z
Publication status	Published - 2018 Sept 1

Bibliographical note

Publisher Copyright:
© 2018, The Author(s).

ASJC Scopus subject areas

General Neuroscience

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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

Jung, H, Park, H, Choi, Y, Kang, H, Lee, E, Kweon, H, Roh, JD, Ellegood, J, Choi, W, Kang, J, Rhim, I, Choi, SY, Bae, M, Kim, SG, Lee, J, Chung, C, Yoo, T, Park, H, Kim, Y, Ha, S, Um, SM, Mo, S, Kwon, Y, Mah, W, Bae, YC, Kim, H, Lerch, JP, Paik, SB & Kim, E 2018, 'Sexually dimorphic behavior, neuronal activity, and gene expression in Chd8-mutant mice', Nature Neuroscience, vol. 21, no. 9, pp. 1218-1228. https://doi.org/10.1038/s41593-018-0208-z

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

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.",

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

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AU - Jung, Hwajin

AU - Park, Haram

AU - Choi, Yeonsoo

AU - Kang, Hyojin

AU - Lee, Eunee

AU - Kweon, Hanseul

AU - Roh, Junyeop Daniel

AU - Ellegood, Jacob

AU - Choi, Woochul

AU - Kang, Jaeseung

AU - Rhim, Issac

AU - Choi, Su Yeon

AU - Bae, Mihyun

AU - Kim, Sun Gyun

AU - Lee, Jiseok

AU - Chung, Changuk

AU - Yoo, Taesun

AU - Park, Hanwool

AU - Kim, Yangsik

AU - Ha, Seungmin

AU - Um, Seung Min

AU - Mo, Seojung

AU - Kwon, Yonghan

AU - Mah, Won

AU - Bae, Yong Chul

AU - Kim, Hyun

AU - Lerch, Jason P.

AU - Paik, Se Bum

AU - Kim, Eunjoon

PY - 2018/9/1

Y1 - 2018/9/1

N2 - 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.

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

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