Multidimensional analysis of behavior predicts genotype with high accuracy in a mouse model of Angelman syndrome

Joseph K. Tanas, Devante D. Kerr, Li Wang, Anika Rai, Ilse Wallaard, Ype Elgersma, Michael S. Sidorov*

*Corresponding author for this work

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Angelman syndrome (AS) is a neurodevelopmental disorder caused by loss of expression of the maternal copy of the UBE3A gene. Individuals with AS have a multifaceted behavioral phenotype consisting of deficits in motor function, epilepsy, cognitive impairment, sleep abnormalities, as well as other comorbidities. Effectively modeling this behavioral profile and measuring behavioral improvement will be crucial for the success of ongoing and future clinical trials. Foundational studies have defined an array of behavioral phenotypes in the AS mouse model. However, no single behavioral test is able to fully capture the complex nature of AS—in mice, or in children. We performed multidimensional analysis (principal component analysis + k-means clustering) to quantify the performance of AS model mice (n = 148) and wild-type littermates (n = 138) across eight behavioral domains. This approach correctly predicted the genotype of mice based on their behavioral profile with ~95% accuracy, and remained effective with reasonable sample sizes (n = ~12–15). Multidimensional analysis was effective using different combinations of behavioral inputs and was able to detect behavioral improvement as a function of treatment in AS model mice. Overall, multidimensional behavioral analysis provides a tool for evaluating the effectiveness of preclinical treatments for AS. Multidimensional analysis of behavior may also be applied to rodent models of related neurodevelopmental disorders, and may be particularly valuable for disorders where individual behavioral tests are less reliable than in AS.

Original languageEnglish
Article number426
JournalTranslational Psychiatry
Issue number1
Publication statusPublished - 3 Oct 2022

Bibliographical note

Funding Information:
This work was supported by the Angelman Syndrome Foundation (ASF) and by the District of Columbia Intellectual and Developmental Disabilities Research Center (DC-IDDRC) Award P50HD105328 by NICHD (PI: V. Gallo). Behavioral experiments performed in the Elgersma lab were funded by the ASF, Associazione Angelman, ZonMW (40-46800-98-009), and SFARI (275234).

Publisher Copyright: © 2022, The Author(s).


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