Neuroanatomy and behavior in mice with a haploinsufficiency of AT-rich interactive domain 1B (ARID1B) throughout development

A A Wade,A Kinman,A Adhikari,S P Petkova,J P Lerch,J L Silverman,J Ellegood,A Creighton,Z Lindenmaier,L M J Nutter,L R Qiu,D Fernandes,A S Nord

doi:10.1186/s13229-021-00432-y

Abstract

BackgroundOne 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 linked to autism spectrum disorder and to affect rare and inherited genetic variation in a broad set of NDDs.MethodsA novel preclinical mouse model of Arid1b deficiency was created and validated to characterize and define neuroanatomical, behavioral and transcriptional phenotypes. Neuroanatomy was assessed ex vivo in adult animals and in vivo longitudinally from birth to adulthood. Behavioral testing was also performed throughout development and tested all aspects of motor, learning, sociability, repetitive behaviors, seizure susceptibility, and general milestones delays.ResultsWe validated decreased Arid1b mRNA and protein in Arid1b+/− mice, with signatures of increased axonal and synaptic gene expression, 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 effect was observed neuroanatomically throughout development. Behaviorally, 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 behaviors were observed. Brains of adult Arid1b+/− mice had a smaller cerebellum and a larger hippocampus and corpus callosum. The corpus callosum increase seen here contrasts previous reports which highlight losses in corpus callosum volume in mice and humans.LimitationsThe behavior and neuroimaging analyses were done on separate cohorts of mice, which did not allow a direct correlation between the imaging and behavioral findings, and the transcriptomic analysis was exploratory, with no validation of altered expression beyond Arid1b.ConclusionsThis 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.

Highlights

One of the causal mechanisms underlying neurodevelopmental disorders (NDDs) is chromatin modification and the genes that regulate chromatin
Validation of reduced AT-rich interactive domain 1B (Arid1b) and broad differential expression signatures in adult cerebellum Quantitative reverse-transcription polymerase chain reaction and Western blot were used to Maximum Forelimb Grip Strength (g-f)
Time (5-min bins) confirm that adult Arid1b+/− mice of both sexes had reduced mRNA and protein levels in cortex and cerebellum samples compared to Arid1b+/+ mice (Fig. 1a–c)

Summary

Introduction

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 linked to autism spectrum disorder and to affect rare and inherited genetic variation in a broad set of NDDs. Neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD) and intellectual disability (ID), are prevalent and pervasive lifelong disorders defined exclusively by behavior. Chromatin modification is thought to be one of the causal mechanisms underlying NDDs, as several chromatin-modifying genes are high-confidence genes with deletions found in numerous cases of ASD. AT-rich interactive domain 1B, ARID1B, and genes in the chromatin modification complex, SWItch/ Sucrose Non-Fermentable (SWI/SNF), are thought to cause Coffin–Siris syndrome (CSS) [6], an exceedingly rare neurodevelopmental disorder with fewer than 200 individuals diagnosed [7]. In a recent report of 143 patients with ARID1B mutations, agenesis or hypoplasia of the corpus callosum was observed in 43% of patients [11]

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Conclusion