Strain-dependence of the Angelman Syndrome phenotypes in Ube3a maternal deficiency mice

Heather A Born,Edwin J Weeber,Shubhangi Mehra,Wai Ling Lee,Natasha M Mehta,An T Dao,Anne E Anderson,Amber T Levine

doi:10.1038/s41598-017-08825-x

Abstract

Angelman syndrome (AS) is a genetic neurodevelopmental disorder, most commonly caused by deletion or mutation of the maternal allele of the UBE3A gene, with behavioral phenotypes and seizures as key features. Currently no treatment is available, and therapeutics are often ineffective in controlling AS-associated seizures. Previous publications using the Ube3a maternal deletion model have shown behavioral and seizure susceptibility phenotypes, however findings have been variable and merit characterization of electroencephalographic (EEG) activity. In this study, we extend previous studies comparing the effect of genetic background on the AS phenotype by investigating the behavioral profile, EEG activity, and seizure threshold. AS C57BL/6J mice displayed robust behavioral impairments, spontaneous EEG polyspikes, and increased cortical and hippocampal power primarily driven by delta and theta frequencies. AS 129 mice performed poorly on wire hang and contextual fear conditioning and exhibited a lower seizure threshold and altered spectral power. AS F1 hybrid mice (C57BL/6J × 129) showed milder behavioral impairments, infrequent EEG polyspikes, and fewer spectral power alterations. These findings indicate the effect of common genetic backgrounds on the Ube3a maternal deletion behavioral, EEG, and seizure threshold phenotypes. Our results will inform future studies on the optimal strain for evaluating therapeutics with different AS-like phenotypes.

Highlights

Angelman Syndrome (AS) is a rare neurogenetic disorder that affects approximately 1 in 20,000 births with an equal incidence rate in genders (National Organization for Rare Disorders)
We found no difference between genotypes on any backgrounds in the anxiety measure of % distance in center area of the Open field assay (OFA) (Fig. 2c) (B6, Wt: 32.98 ± 2.536%, Angelman syndrome (AS): 28.17 ± 2.07%; 129, Wt: 5.360 ± 1.442%, AS: 12.62 ± 4.756%; F1, Wt: 14.85 ± 2.719%, AS: 16.67 ± 3.612%)
Genetic mouse models of AS recapitulate both abnormal behavioral phenotypes and epileptiform activity, and are important for testing potential therapies as well as understanding the molecular mechanisms underlying AS phenotypes for directing therapeutic discovery

Summary

Introduction

Angelman Syndrome (AS) is a rare neurogenetic disorder that affects approximately 1 in 20,000 births with an equal incidence rate in genders (National Organization for Rare Disorders). The varying results found previously in AS mice suggest a need for in-depth characterization of the model to determine the optimal measures by which to evaluate AS biomarkers and potential rescue of these phenotypes with novel therapeutics Both models show almost no Ube3a protein expression in the brain of maternal-deficient mice, Miura et al.[13] used an AS model with a mutation targeting different exons than the model used in this study, which was developed by Jiang et al.[9], which should be taken into account when comparing previous studies characterizing behavioral and seizure phenotypes as the difference in mutation may affect phenotype expression. Our findings are important for future studies in the context of screening novel therapeutics using this AS mouse model

Methods

Results

Conclusion