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

Abstract

Chd8+/N2373K mice with a human C-terminal-truncating mutation (N2373K) display autistic-like behaviors in juvenile and adult males but not in females. In contrast, Chd8+/S62X mice with a human N-terminal-truncating mutation (S62X) display behavioral deficits in juvenile males (not females) and adult males and females, indicative of age-differential sexually dimorphic behaviors. Excitatory synaptic transmission is suppressed and enhanced in male and female Chd8+/S62X juveniles, respectively, but similarly enhanced in adult male and female mutants. ASD-like transcriptomic changes are stronger in newborn and juvenile (but not adult) Chd8+/S62X males but in newborn and adult (not juvenile) Chd8+/S62X females. These results point to age-differential sexual dimorphisms in Chd8+/S62X mice at synaptic and transcriptomic levels, in addition to the behavioral level.

Male-Dominant Effects of Chd8 Haploinsufficiency on Synaptic Phenotypes during Development in Mouse Prefrontal Cortex

“…9 However, transcriptome analysis of the Chd8 +/S62X mice suggested different age-specific alterations in males versus females. 25 While a female protective effect is consistent with observations of more disruptive genetic variants found among female autistic individuals, 35 it is highly likely that sexually dimorphic liability thresholds are established through the combined effects of risk potentiation in males and attenuation in females. Further explorations of the molecular mechanisms underlying these changes at the cellular level may therefore reveal key mechanisms that give rise to sexual dimorphism more generally in Chd8 haploinsufficiency.…”

“…Transcriptome analyses in Chd8 +/N2373K mice have further demonstrated greater differences in transcriptomes in female brains, which may suggest a female protective biological mechanism at play . However, transcriptome analysis of the Chd8 +/S62X mice suggested different age-specific alterations in males versus females . While a female protective effect is consistent with observations of more disruptive genetic variants found among female autistic individuals, it is highly likely that sexually dimorphic liability thresholds are established through the combined effects of risk potentiation in males and attenuation in females.…”

“…24 Interestingly, sex differential synaptic changes to excitatory transmission in CA1 neurons of the hippocampus were seen in juveniles. 25 Together, these studies suggested that sexually dimorphic behaviors and synaptic phenotypes can differ substantially in mice with different Chd8 mutations. However, a systematic examination of sexual dimorphism in excitatory and inhibitory synapses across multiple developmental stages to identify a potential key window has not been done, nor have the inputs into the key output neurons of the mPFC been examined.…”

“…Interestingly, no sex differences were seen in the superficial layers of the medial PFC (mPFC). Recent work by the same group investigated the phenotypes of mice with a different ASD-associated mutation in Chd8 , Chd8 +/S62X . , In mice heterozygous for this mutation, changes affecting repetitive and anxiety-like behaviors were found in both sexes in adults, whereas only male juvenile mice exhibited behavioral alterations . Interestingly, sex differential synaptic changes to excitatory transmission in CA1 neurons of the hippocampus were seen in juveniles .…”

Neurodevelopmental functions of CHD8: new insights and questions

“…Given that ASD is diagnosed based on social and communication difficulties and the presence of restrictive and repetitive behaviours, a lot of research efforts have focused on the behavioural characterisation of Chd8 +/ − mouse models. All groups reported behavioural phenotypes in Chd8 +/ − mice, but the reported phenotypes were not always consistent [ 11–16 , 19 , 22 ]. Intriguingly, the Kim group showed that two different ASD-associated nonsense (frameshift) mutations in Chd8 , Chd8 +/N2373K and Chd8 +/S62X [ 14 , 22 ], resulted in different behavioural phenotypes.…”