Neuroanatomy and behavior in mice with a haploinsufficiency of AT-rich interactive domain 1B (ARID1B) throughout development.
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 linked to autism spectrum disorder 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, 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.


RESULTS
We 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.


LIMITATIONS
The 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.


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.
['Ellegood|J|J|0000-0003-1504-3321', 'Petkova|S P|SP|', 'Kinman|A|A|', 'Qiu|L R|LR|', 'Adhikari|A|A|', 'Wade|A A|AA|', 'Fernandes|D|D|', 'Lindenmaier|Z|Z|', 'Creighton|A|A|', 'Nutter|L M J|LMJ|', 'Nord|A S|AS|', 'Silverman|J L|JL|', 'Lerch|J P|JP|']
D000818:Animals D001522:Behavior, Animal D001921:Brain D005106:Exploratory Behavior D005239:Fear D005260:Female D005684:Gait D057895:Haploinsufficiency D007858:Learning D008279:Magnetic Resonance Imaging D008297:Male D008817:Mice, Mutant Strains D009048:Motor Skills D065886:Neurodevelopmental Disorders D021641:Recognition, Psychology D012919:Social Behavior D014157:Transcription Factors D014828:Vocalization, Animal
Behavior Arid1b Autism Mouse Coffin–Siris syndrome Magnetic resonance imaging