Aberrant aggressive behavior in a mouse model of Angelman syndrome

Lilach Simchi,Hanoch Kaphzan

doi:10.1038/s41598-020-79984-7

Abstract

Angelman syndrome (AS) is a genetic neurodevelopmental disorder due to the absence of the E3-ligase protein, UBE3A. Inappropriate social interactions, usually hyper-sociability, is a part of that syndrome. In addition, clinical surveys and case reports describe aggressive behavior in AS individuals as a severe difficulty for caretakers. A mouse model for AS recapitulates most of the human AS phenotypes. However, very few studies utilized this mouse model for investigating affiliative social behavior, and not even a single study examined aggressive behavior. Hence, the aim of the herein study was to examine affiliative and aggressive social behavior. For that, we utilized a battery of behavioral paradigms, and performed detailed analyses of these behaviors. AS mice exhibited a unique characteristic of reduced habituation towards a social stimulus in comparison to their wild-type (WT) littermates. However, overall there were no additional marked differences in affiliative social behavior. In contrast to the mild changes in affiliative behavior, there was a striking enhanced aggression in the AS mice compared to their WT littermates. The herein findings emphasize the use of AS mouse model in characterizing and measuring inappropriate aggressive behavior, and suggests these as tools for investigating therapeutic interventions aimed at attenuating aggressive behavior.

Highlights

Angelman syndrome (AS) is a genetic neurodevelopmental disorder due to the absence of the E3-ligase protein, ubiquitin-protein ligase E3A gene (UBE3A)
Model mice recapitulate the hyper-sociability phenotype observed in AS-affected humans, we tested their preference to interact with a social stimulus over a non-social one, utilizing the three-chamber social test (Fig. 1a)
Inherited maternal duplications and triplications of the sequence encompassing UBE3A gene (15q11–13), where UBE3A is overexpressed, are amongst the most common genome copy number variations observed in A SD42

Summary

Introduction

Angelman syndrome (AS) is a genetic neurodevelopmental disorder due to the absence of the E3-ligase protein, UBE3A. Very few studies utilized this mouse model for investigating affiliative social behavior, and not even a single study examined aggressive behavior. The aim of the study was to examine affiliative and aggressive social behavior. Previous studies showed that these mouse models recapitulate the various phenotypes found in humans with AS, such as motor dysfunction, susceptibility for seizures, and cognitive d eficits[23,24,25,26]. While cognitive AS hippocampal-dependent deficits and motor performance have been extensively studied in AS mouse models, the striking social behavior characteristics associated with AS have been mostly neglected. The study aimed to comprehensively characterize elements of both affiliative (sociability) and agonistic (offensive aggression) social behaviors in AS mouse model. We delineated additional essential social abilities, such as social recognition and social habituation

Methods

Results

Conclusion