Age-differential sexual dimorphism in CHD8-S62X-mutant mouse behaviors

Abstract

Autism spectrum disorders (ASD) are ~4-times more common in males than females, and CHD8 (a chromatin remodeler)-related ASD shows a strong male bias (~4:1), although the underlying mechanism remains unclear. Chd8-mutant mice with a C-terminal protein-truncating mutation (N2373K) display male-preponderant behavioral deficits as juveniles and adults, although whether this also applies to other Chd8 mutations remains unknown. In addition, it remains unclear whether sexually dimorphic phenotypes in Chd8-mutant mice are differentially observed in males and females across different ages. We here generated new Chd8-mutant (knock-in) mice carrying a patient-derived mutation causing an N-terminal and stronger protein truncation (Chd8+/S62X mice) and characterized the mice by behavioral analyses. Juvenile Chd8+/S62X mice displayed male-preponderant autistic-like behaviors; hypoactivity and enhanced mother-seeking/attachment behavior in males but not in females. Adult male and female Chd8+/S62X mice showed largely similar deficits in repetitive and anxiety-like behavioral domains. Therefore, the CHD8-S62X mutation induces ASD-like behaviors in juvenile male mice and adult male and female mice, pointing to an age-differential sexual dimorphism and also distinct sexual dimorphisms in different Chd8 mutations (N2373K and S62X).

Age-differential sexual dimorphisms in CHD8-S62X-mutant mouse synapses and transcriptomes

“…To determine whether the similarly altered behaviors in adult Chd8 +/S62X males and females ( Lee et al, 2022 ) accompany synaptic dysfunctions, we measured synaptic transmissions in the adult hippocampus, a brain region associated with ASD ( Schumann et al, 2004 ).…”

“…Chd8 +/S62X mice have been recently reported ( Lee et al, 2022 ). Mice were maintained at the Korea Advanced Institute of Science and Technology (KAIST) mouse facility (12-h light–dark cycle).…”

“…Previous studies on Chd8 -mutant mice and human neurons suggested multiple mechanisms that may underlie CHD8-related brain deficits ( Sugathan et al, 2014 ; Cotney et al, 2015 ; Wang et al, 2015 ; Breuss and Gleeson, 2016 ; Durak et al, 2016 ; Katayama et al, 2016 ; Gompers et al, 2017 ; Platt et al, 2017 ; Wang et al, 2017 ; Andreae and Basson, 2018 ; Jung et al, 2018 ; Suetterlin et al, 2018 ; Wade et al, 2018 ; Xu et al, 2018 ; Zhao et al, 2018 ; Hulbert et al, 2020 ; Jimenez et al, 2020 ; Sood et al, 2020 ; Cherepanov et al, 2021 ; Ding et al, 2021 ; Ellingford et al, 2021 ; Hurley et al, 2021 ; Kawamura et al, 2021 ; Kweon et al, 2021 ; Weissberg and Elliott, 2021 ; Chen et al, 2022 ; Coakley-Youngs et al, 2022 ; Dong et al, 2022 ; Haddad Derafshi et al, 2022 ; Jimenez et al, 2022 ; Kerschbamer et al, 2022 ; Lee et al, 2022 ; Paulsen et al, 2022 ; Thudium et al, 2022 ; Tu et al, 2022 ; Villa et al, 2022 ; Yu et al, 2022 ; Hayot et al, 2023 ). However, mechanisms underlying the male–female differences in CHD8-related ASD are poorly understood ( Jung et al, 2018 ; Cherepanov et al, 2021 ; Yu et al, 2022 ).…”

“…Chd8 +/N2373K mice that carry a human mutation that leads to a C-terminal protein truncation (N2373K; O’Roak et al, 2012 ; Merner et al, 2016 ) display male-preponderant behavioral deficits as juveniles and adults. In contrast, Chd8 +/S62X mice expressing CHD8-S62X proteins with N-terminal truncation ( O’Roak et al, 2012 ) display behavioral deficits in juvenile males (not females) and adult males and females ( Lee et al, 2022 ), indicative of age-differential sexually dimorphic behaviors. Here, we characterized and compared synaptic and transcriptomic phenotypes in male and female Chd8 +/S62X mice at juvenile and adult stages, which led us to find age-differential sexual dimorphisms at synaptic and transcriptomic levels additional to the behavioral level.…”

Sex-Related Changes in the Clinical, Genetic, Electrophysiological, Connectivity, and Molecular Presentations of ASD: A Comparison between Human and Animal Models of ASD with Reference to Our Data

“…Chd8 -mutant mice (knock-in) with a human C-terminal protein-truncating mutation ( N2373K ) demonstrated male-preponderant behavioral deficits, evaluated at birth, juvenile, and adult stages [ 115 ]. Moreover, these ASD-like behaviors were accompanied by elevated neuronal activation in the hippocampus and prefrontal cortex under stressful conditions and changes in pups in ultrasonic vocalization [ 115 ] as well as altered neuronal, synaptic, and transcriptomic phenotypes [ 117 , 118 ]. In contrast, reduced brain baseline activity was found in females, which normalized upon maternal separation [ 115 ].…”