Background Angelman syndrome (AS) is a single-gene neurodevelopmental disorder caused by loss of function of the maternal copy of the UBE3A gene. Nearly all individuals with AS lack speech, resulting in major impacts on daily life for patients and caregivers. To evaluate new therapies for AS, it is crucial to have a mouse model that characterizes meaningful clinical features. Vocalizations are used in many contexts in mice, including pup retrieval, social interactions, courtship, and distress. Previous work in the Ube3am−/p+ mouse model of AS found abnormalities in the number of ultrasonic vocalizations (USVs) mice produced during pup isolation and same-sex social interactions. Here, we evaluated Ube3am−/p+ vocalizations during courtship and distress. Quantifying USVs in these contexts enables comparison of USVs in social (courtship) and non-social (distress) settings. In addition, we assessed the utility of incorporating USV testing into existing Ube3am−/p+ mouse behavioral assessments used to evaluate potential AS treatments. Methods We used multiple behavioral paradigms to evaluate courtship vocalizations and tail suspension tests to evaluate distress vocalizations in adult wild-type (WT) and Ube3am−/p+ littermates, and quantified USV properties using the program DeepSqueak. A subset of mice also performed an established Ube3am−/p+ behavioral battery that included rotarod, open field, marble burying, and nest building. We used principal component analysis to evaluate the value of USV testing in this cohort in the context of other behaviors. Results In both social courtship and nonsocial distress behavioral paradigms, Ube3am−/p+ mice made fewer USVs compared to WT mice. Spectral properties of USVs were abnormal in Ube3am−/p+ mice on courtship tests but mostly typical on distress tests. Including USVs in the Ube3am−/p+ mouse behavior battery increased the distance between Ube3am−/p+ and WT clusters in principal component space. Conclusions Ube3am−/p+ mice have disrupted USV production in social and nonsocial contexts. Spectral properties of USVs are most impacted in the social courtship context. Adding USVs to the Ube3am−/p+ behavior battery may improve sensitivity to detect group differences and changes in communication.

Courtship and distress ultrasonic vocalizations are altered in a mouse model of Angelman syndrome

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2025年10月1日

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Caleigh D. Guoynes,
Grace Pavalko,
Michael S. Sidorov

摘要

Background

Angelman syndrome (AS) is a single-gene neurodevelopmental disorder caused by loss of function of the maternal copy of the UBE3A gene. Nearly all individuals with AS lack speech, resulting in major impacts on daily life for patients and caregivers. To evaluate new therapies for AS, it is crucial to have a mouse model that characterizes meaningful clinical features. Vocalizations are used in many contexts in mice, including pup retrieval, social interactions, courtship, and distress. Previous work in the Ube3a^m−/p+ mouse model of AS found abnormalities in the number of ultrasonic vocalizations (USVs) mice produced during pup isolation and same-sex social interactions. Here, we evaluated Ube3a^m−/p+ vocalizations during courtship and distress. Quantifying USVs in these contexts enables comparison of USVs in social (courtship) and non-social (distress) settings. In addition, we assessed the utility of incorporating USV testing into existing Ube3a^m−/p+ mouse behavioral assessments used to evaluate potential AS treatments.

Methods

We used multiple behavioral paradigms to evaluate courtship vocalizations and tail suspension tests to evaluate distress vocalizations in adult wild-type (WT) and Ube3a^m−/p+ littermates, and quantified USV properties using the program DeepSqueak. A subset of mice also performed an established Ube3a^m−/p+ behavioral battery that included rotarod, open field, marble burying, and nest building. We used principal component analysis to evaluate the value of USV testing in this cohort in the context of other behaviors.

Results

In both social courtship and nonsocial distress behavioral paradigms, Ube3a^m−/p+ mice made fewer USVs compared to WT mice. Spectral properties of USVs were abnormal in Ube3a^m−/p+ mice on courtship tests but mostly typical on distress tests. Including USVs in the Ube3a^m−/p+ mouse behavior battery increased the distance between Ube3a^m−/p+ and WT clusters in principal component space.

Conclusions

Ube3a^m−/p+ mice have disrupted USV production in social and nonsocial contexts. Spectral properties of USVs are most impacted in the social courtship context. Adding USVs to the Ube3a^m−/p+ behavior battery may improve sensitivity to detect group differences and changes in communication.