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

被引：107

作者：

Jung, Hwajin ^{[1
]}

Park, Haram ^{[2
]}

Choi, Yeonsoo ^{[2
]}

Kang, Hyojin ^{[3
]}

Lee, Eunee ^{[1
]}

Kweon, Hanseul ^{[2
]}

Roh, Junyeop Daniel ^{[2
]}

Ellegood, Jacob ^{[4
]}

Choi, Woochul ^{[5
]}

Kang, Jaeseung ^{[2
]}

Rhim, Issac ^{[1
]}

Choi, Su-Yeon ^{[1
]}

Bae, Mihyun ^{[1
]}

Kim, Sun-Gyun ^{[1
]}

Lee, Jiseok ^{[1
]}

Chung, Changuk ^{[2
]}

Yoo, Taesun ^{[2
]}

Park, Hanwool ^{[6
]}

Kim, Yangsik ^{[6
]}

Ha, Seungmin ^{[2
]}

Um, Seung Min ^{[2
]}

Mo, Seojung ^{[7
,8
]}

Kwon, Yonghan ^{[2
]}

Mah, Won ^{[9
]}

Bae, Yong Chul ^{[9
]}

Kim, Hyun ^{[7
,8
]}

Lerch, Jason P. ^{[4
,10
]}

Paik, Se-Bum ^{[5
]}

Kim, Eunjoon ^{[1
,2
]}

机构：

[1] Inst for Basic Sci Korea, Ctr Synapt Brain Dysfunct, Daejeon, South Korea

[2] Korea Adv Inst Sci & Technol, Dept Biol Sci, Daejeon, South Korea

[3] KISTI, Supercomp Ctr, Daejeon, South Korea

[4] Hosp Sick Children, Mouse Imaging Ctr, Toronto, ON, Canada

[5] Korea Adv Inst Sci & Technol, Dept Bio & Brain Engn, Program Brain & Cognit Engn, Daejeon, South Korea

[6] Korea Adv Inst Sci & Technol, Grad Sch Med Sci & Engn, Daejeon, South Korea

[7] Korea Univ, Dept Anat, Coll Med, Seoul, South Korea

[8] Korea Univ, Div Brain Korea 21, Coll Med, Biomed Sci, Seoul, South Korea

[9] Kyungpook Natl Univ, Sch Dent, Dept Anat & Neurobiol, Daegu, South Korea

[10] Univ Toronto, Dept Med Biophys, Toronto, ON, Canada

来源：

NATURE NEUROSCIENCE | 2018年 / 21卷 / 09期

关键词：

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

D O I：

10.1038/s41593-018-0208-z

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

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.

引用

页码：1218 / +

页数：15

共 73 条

[61] Transcriptomic analysis of autistic brain reveals convergent molecular pathology [J].

Voineagu, Irina ;

Wang, Xinchen ;

Johnston, Patrick ;

Lowe, Jennifer K. ;

Tian, Yuan ;

Horvath, Steve ;

Mill, Jonathan ;

Cantor, Rita M. ;

Blencowe, Benjamin J. ;

Geschwind, Daniel H. .

NATURE, 2011, 474 (7351) :380-+

[62] Gene expression in human brain implicates sexually dimorphic pathways in autism spectrum disorders [J].

Werling, Donna M. ;

Parikshak, Neelroop N. ;

Geschwind, Daniel H. .

NATURE COMMUNICATIONS, 2016, 7

[63] Recurrence rates provide evidence for sex-differential, familial genetic liability for autism spectrum disorders in multiplex families and twins [J].

Werling, Donna M. ;

Geschwind, Daniel H. .

MOLECULAR AUTISM, 2015, 6

[64] Replication of linkage at chromosome 20p13 and identification of suggestive sex-differential risk loci for autism spectrum disorder [J].

Werling, Donna M. ;

Lowe, Jennifer K. ;

Luo, Rui ;

Cantor, Rita M. ;

Geschwind, Daniel H. .

MOLECULAR AUTISM, 2014, 5

[65] Understanding sex bias in autism spectrum disorder [J].

Werling, Donna M. ;

Geschwind, Daniel H. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2013, 110 (13) :4868-4869

[66] Sex differences in autism spectrum disorders [J].

Werling, Donna M. ;

Geschwind, Daniel H. .

CURRENT OPINION IN NEUROLOGY, 2013, 26 (02) :146-153

[67] Anxiety in children and adolescents with autism spectrum disorders [J].

White, Susan W. ;

Oswald, Donald ;

Ollendick, Thomas ;

Scahill, Lawrence .

CLINICAL PSYCHOLOGY REVIEW, 2009, 29 (03) :216-229

[68] The autism-associated gene chromodomain helicase DNA-binding protein 8 (CHD8) regulates noncoding RNAs and autism-related genes [J].

Wilkinson, B. ;

Grepo, N. ;

Thompson, B. L. ;

Kim, J. ;

Wang, K. ;

Evgrafov, O. V. ;

Lu, W. ;

Knowles, J. A. ;

Campbell, D. B. .

TRANSLATIONAL PSYCHIATRY, 2015, 5 :e568-e568

[69]

Yang Mu, 2009, Curr Protoc Neurosci, VChapter 8, DOI 10.1002/0471142301.ns0824s48

[70] Neocortical excitation/inhibition balance in information processing and social dysfunction [J].

Yizhar, Ofer ;

Fenno, Lief E. ;

Prigge, Matthias ;

Schneider, Franziska ;

Davidson, Thomas J. ;

O'Shea, Daniel J. ;

Sohal, Vikaas S. ;

Goshen, Inbal ;

Finkelstein, Joel ;

Paz, Jeanne T. ;

Stehfest, Katja ;

Fudim, Roman ;

Ramakrishnan, Charu ;

Huguenard, John R. ;

Hegemann, Peter ;

Deisseroth, Karl .

NATURE, 2011, 477 (7363) :171-178

← 1 2 3 4 5 6 7 8 →