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Prefrontal cortex transcriptome of Arid1b heterozygote mutation mice age of postnatal day 10

ABSTRACT: Arid1b is a chromatin remodeler implicated in neurodevelopmental disorders. Arid1b mutant mice with haploinsufficiency (Arid1b HT) displayed persistent excitatory synaptic dysfunction from juvenile to adult stage, decreased synaptic density and transmission. Moreover, they showed autistic-like behaviors in both of early and adult stages, decreased sociability in pup USV calling and adult social interaction, and adult repetitive grooming. To investigate early transcriptomic changes in Arid1b mutant mice, RNAseq analysis of prefrontal cortex from wild-type and Arid1b mutant mice at postnatal day 10 was done. Transcriptomic changes support these electrophysiological and behavioral deficits. Arid1b HT mice at postnatal day 10 showed alterations in genes implicated in synaptic functions and ASD.

ORGANISM(S): Mus musculus

PROVIDER: GSE203249 | GEO | 2022/07/21

REPOSITORIES: GEO

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Project description:Background - One of the causal mechanisms underlying neurodevelopmental disorders (NDDs) is chromatin modification, and the genes that regulate chromatin. AT-Rich Interactive Domain 1B (ARID1B), a chromatin modifier, has been shown to be reduced in autism spectrum disorder (ASD) and to affect rare and inherited genetic variation in a broad set of NDDs. Methods - A novel preclinical mouse model of Arid1b deficiency was created and validated to characterize and define neuroanatomical, behavioural and tran¬scriptional phenotypes. Neuroanatomy was assessed ex vivo in adult animals and in vivo longitudinally from birth to adulthood. Behavioural testing was also performed throughout development and tested all aspects of motor, learning, sociability, repetitive behaviours, seizure susceptibility and general milestones delays. Results – We validated decreased Arid1b mRNA and protein in Arid1b+/- mice, with signatures of increased axonal and synaptic gene expression and decreased transcriptional regulator and RNA processing expression in adult Arid1b+/- cerebellum. During neonatal development, Arid1b+/- mice exhibited robust impairments in ultrasonic vocalizations (USVs) and metrics of developmental growth. In addition, a striking sex dependence was observed throughout development; males had an early emergence of this neuroanatomical phenotype at postnatal day 7, whereas females had a delayed emergence around postnatal day 40. Behaviourally, as adults, Arid1b+/- mice showed low motor skills in open field exploration and normal three chambered approach. Arid1b+/- mice had learning and memory deficits in novel object recognition but not in visual discrimination and reversal touchscreen tasks. Social interactions in the male-female social dyad with USVs revealed social deficits on some but not all parameters. No repetitive behaviours were observed. Brains of adult Arid1b+/- mice had a smaller cerebellum and a larger hippocampus and corpus callosum. These results stand in contrast to previously reported data highlighting losses in corpus callosum volume in mice. Limitations – The behaviour and neuroimaging analyses were done on separate cohorts of mice, which did not allow a direct correlation between the imaging and behavioural findings, and the transcriptomic analyses was exploratory, with no validation of altered expression beyond Arid1b. Conclusions – This study represents a full validation and investigation of a novel model of Arid1b+/- haploinsufficiency throughout development and highlights the importance of examining both sexes throughout development in NDDs.

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Prefrontal cortex transcriptome of Arid1b heterozygote mutation mice age of postnatal day 10

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