Spectrum of social alterations in the Neurobeachin haploinsufficiency mouse model of autism

Abstract

Autism spectrum disorder (ASD) is a common and pervasive neurodevelopmental disorder, characterized by sexually divergent social deficits. Its etiology is multifactorial with an important contribution of genetic factors. Neurobeachin (Nbea), a brain-enriched multidomain scaffolding protein, is an ASD candidate gene that was found to be translocated or deleted in ASD patients. Nbea haploinsufficient (^+/-) mice have been proposed as an ASD mouse model, but its broad-spectrum social phenotype, sexual divergence and age-related robustness remain unstudied. This study compared one-year-old male and female Nbea^+/- mice and their control littermates in an extensive behavioral battery that focused on social behaviors and communication. Nbea haploinsufficiency was associated with selective, sex-dependent, quantitative and qualitative changes, including alterations in social interest and approach, ultrasonic vocalization (USV) between same-sex adult conspecifics, and preferred types of social interaction. Notably, Nbea^+/- females (but not males) displayed a significantly higher number of calls, and the mean principal frequency of their calls was higher than those of normal female littermates. Our results demonstrate that Nbea haploinsufficiency alters various aspects of social performance that are also altered in clinical ASD. The phenotype was often different between male and female mice, even though this sexual divergence was sometimes counterintuitive to observations in people with ASD, and probably influenced by differences in social interaction between male and female mice. By and large, however, this study demonstrates the clinical validity and robustness of the ASD-like phenotype of Nbea^+/- mice.

Keywords: Autism spectrum disorder (ASD); Behavioral phenotyping; Mouse model; Neurobeachin (Nbea); Social interaction; Ultrasonic vocalization (USV).