Behavioral Evaluation of Angelman Syndrome Mice at Older Ages

Rebecca Dutta,Jacqueline N Crawley

doi:10.1016/j.neuroscience.2019.10.027

Abstract

Angelman syndrome is a neurodevelopmental disorder presenting with severe deficits in motor, speech, and cognitive abilities. The primary genetic cause of Angelman syndrome is a maternally transmitted mutation in the Ube3a gene, which has been successfully modeled in Ube3a mutant mice. Phenotypes have been extensively reported in young adult Ube3a mice. Because symptoms continue throughout life in Angelman syndrome, we tested multiple behavioral phenotypes of male Ube3a mice and WT littermate controls at older adult ages. Social behaviors on both the 3-chambered social approach and male–female social interaction tests showed impairments in Ube3a at 12 months of age. Anxiety-related scores on both the elevated plus-maze and the light ↔ dark transitions assays indicated anxiety-like phenotypes in 12 month old Ube3a mice. Open field locomotion parameters were consistently lower at 12 months. Reduced general exploratory locomotion at this age prevented the interpretation of an anxiety-like phenotype, and likely impacted social tasks. Robust phenotypes in middle-aged Ube3a mice appear to result from continued motor decline. Motor deficits may provide the best outcome measures for preclinical testing of pharmacological targets, towards reductions of symptoms in adults with Angelman syndrome.

Highlights

Angelman syndrome is a rare genetic neurodevelopmental disorder characterized by severe intellectual disabilities, impaired speech, developmental delays, microcephaly, seizures, anxiety, motor dysfunctions, ataxic gait, social communication deficits, and a happy demeanor with excessive laughter (Angelman, 1965; Williams et al, 2010; Bird, 2014; Wheeler et al, 2017; den Bakker et al, 2018; www.angelman.org)
Lower open field locomotor activity on all parameters was highly significant in Ube3a mice at 12 months of age, extending previous findings at younger ages (Allensworth et al, 2011; Huang et al, 2013; Ciarlone et al, 2017; Sonzogni et al, 2018)
Interpretations of anxiety-related phenotypes appear to be confounded by the motor deficits in older Ube3a mice

Summary

Introduction

Angelman syndrome is a rare genetic neurodevelopmental disorder characterized by severe intellectual disabilities, impaired speech, developmental delays, microcephaly, seizures, anxiety, motor dysfunctions, ataxic gait, social communication deficits, and a happy demeanor with excessive laughter (Angelman, 1965; Williams et al, 2010; Bird, 2014; Wheeler et al, 2017; den Bakker et al, 2018; www.angelman.org). The primary genetic cause of Angelman syndrome resides in the deletion of a sequence of imprinted genes at chromosomal locus 15q11-q13. Mouse models incorporating the loss of maternal Ube3a have been generated and wellcharacterized for several behavioral features relevant to the symptoms of Angelman syndrome, including motor and cognitive deficits (Jiang et al, 1999; 2010; Heck et al, 2008; Mabb et al, 2011; Baudry et al, 2012; Kaphzan et al, 2012; Jana, 2012; Huang et al, 2013; Santini et al, 2015; Leach and Crawley, 2018; Sonzogni et al, 2018). Ube3a mutant mouse models provide a preclinical research tool for the discovery of effective therapeutics for Angelman syndrome (van Woerden et al, 2007; Huang et al, 2011; Egawa et al, 2012; Margolis et al, 2015; Beaudet and Meng, 2016; Bi et al, 2016; Tan and Bird, 2016; Ciarloni et al, 2017; Stoppel and Anderson, 2017; Guzzetti et al, 2018; Rotaru et al, 2018; Lee et al, 2018)

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