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

Molecular Autism

A. Adhikari¹  J. L. Silverman¹  S. P. Petkova²  A. S. Nord³  A. Kinman⁴  J. Ellegood⁴  D. Fernandes⁵  Z. Lindenmaier⁵  J. P. Lerch⁶  A. A. Wade⁷  L. M. J. Nutter⁸  A. Creighton⁸  L. R. Qiu⁹ 

[1] Department of Psychiatry and Behavioral Sciences, MIND Institute, School of Medicine, University of California, Davis, Sacramento, CA, USA;Department of Psychiatry and Behavioral Sciences, MIND Institute, School of Medicine, University of California, Davis, Sacramento, CA, USA;Neuroscience Graduate Group, University of California - Davis, Davis, CA, USA;Department of Psychiatry and Behavioral Sciences, MIND Institute, School of Medicine, University of California, Davis, Sacramento, CA, USA;Neuroscience Graduate Group, University of California - Davis, Davis, CA, USA;Department of Neurobiology, Physiology and Behavior, University of California - Davis, Davis, CA, USA;Mouse Imaging Centre (MICe), Hospital for Sick Children, 25 Orde Street, M5T 3H7, Toronto, ON, Canada;Mouse Imaging Centre (MICe), Hospital for Sick Children, 25 Orde Street, M5T 3H7, Toronto, ON, Canada;Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada;Mouse Imaging Centre (MICe), Hospital for Sick Children, 25 Orde Street, M5T 3H7, Toronto, ON, Canada;Wellcome Centre for Integrative Neuroimaging, FMRIB, Nuffield Department of Clinical Neuroscience, The University of Oxford, Oxford, UK;Neuroscience Graduate Group, University of California - Davis, Davis, CA, USA;The Centre for Phenogenomics, Hospital for Sick Children, Toronto, ON, Canada;Wellcome Centre for Integrative Neuroimaging, FMRIB, Nuffield Department of Clinical Neuroscience, The University of Oxford, Oxford, UK;

关键词: Magnetic resonance imaging;    Coffin–Siris syndrome;    Autism;    Arid1b;    Mouse;    Behavior;   

DOI  :  10.1186/s13229-021-00432-y

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY