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Nat Neurosci. 2018 Sep;21(9):1218-1228. doi: 10.1038/s41593-018-0208-z. Epub 2018 Aug 13.

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

Author information

1
Center for Synaptic Brain Dysfunctions, Institute for Basic Science (IBS), Daejeon, Korea.
2
Department of Biological Sciences, Korea Advanced Institute for Science and Technology (KAIST), Daejeon, Korea.
3
Supercomputing Center, KISTI, Daejeon, Korea.
4
Mouse Imaging Centre, Hospital for Sick Children, Toronto, Ontario, Canada.
5
Program of Brain and Cognitive Engineering, Department of Bio and Brain Engineering, KAIST, Daejeon, Korea.
6
Graduate School of Medical Science and Engineering, KAIST, Daejeon, Korea.
7
Department of Anatomy and Division of Brain Korea 21, Biomedical Science, College of Medicine, Korea University, Seoul, Korea.
8
Department of Anatomy and Neurobiology, School of Dentistry, Kyungpook National University, Daegu, Korea.
9
Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
10
Center for Synaptic Brain Dysfunctions, Institute for Basic Science (IBS), Daejeon, Korea. kime@kaist.ac.kr.
11
Department of Biological Sciences, Korea Advanced Institute for Science and Technology (KAIST), Daejeon, Korea. kime@kaist.ac.kr.

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.

PMID:
30104731
DOI:
10.1038/s41593-018-0208-z
[Indexed for MEDLINE]

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