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

Abstract

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.

Inability to switch from ARID1A-BAF to ARID1B-BAF impairs exit from pluripotency and commitment towards neural crest formation inARID1B-related neurodevelopmental disorders

“…Therefore, we speculate that the dysregulation of neuroectoderm specification caused by ARID1B mutations may underlie both the cognitive impairment and craniofacial abnormalities that are typical of Coffin-Siris syndrome. This model is further supported by a significant overlap of differentially expressed genes identified in our study (neural crest formation) and in a recently published ARID1B-KO mouse model (brain tissue) 30 .…”

“…Finally, we looked for potential overlap between our set of 2,356 differentially expressed genes at day 5 of iPSC differentiation toward CNCC and a set of genes identified as differentially expressed in a recent RNA-seq study which compared cerebellar tissue of ARID1B +/and ARID1B-wt mice 30 . Notably, 1,297 of the 2,356 genes (55%) found as differentially expressed in our study were also found as differentially expressed in the KO-mouse model dataset.…”

Insulin-like growth factor-2 does not improve behavioral deficits in mouse and rat models of Angelman Syndrome

“…Susceptibility to primary generalized seizures was behaviorally assessed by systemically administering 80 mg/kg pentylenetetrazol (PTZ; a GABA A receptor antagonist) via intraperitoneal injection and observing the timing and progression of the subsequent convulsions following a protocol described previously [ 58 , 66 , 67 ]. Immediately following injection of PTZ, animals were individually placed in a clean empty standard mouse cage (27 cm l × 16.5 cm w × 12.5 cm h) and watched carefully by a trained observer blinded to genotype and treatment condition.…”

Insulin-like growth factor-2 does not improve behavioral deficits in mouse and rat models of Angelman Syndrome

“…Pentylenetetrazol-induced seizures. Susceptibility to primary generalized seizures was behaviorally assessed by systemically administering 80 mg/kg pentelenetetrazol (PTZ; a GABA A receptor antagonist) via intraperitoneal injection and observing the timing and progression of the subsequent convulsions following a protocol described previously [55,63,64]. Immediately following injection of PTZ, animals were individually placed in a clean empty standard mouse cage (27 cm l x 16.5 cm w x 12.5 cm h) and watched carefully by a trained observer blinded to genotype and treatment condition.…”