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

## TL;DR

A mouse model of Angelman syndrome shows reduced and abnormal ultrasonic vocalizations during courtship and distress, suggesting communication difficulties that could help assess treatments.

## Contribution

The study introduces courtship and distress ultrasonic vocalizations as new behavioral metrics in the Ube3am−/p+ mouse model of Angelman syndrome.

## Key findings

- Ube3am−/p+ mice produce fewer ultrasonic vocalizations than wild-type mice in both courtship and distress contexts.
- Spectral properties of ultrasonic vocalizations are abnormal in Ube3am−/p+ mice during courtship but not distress.
- Including ultrasonic vocalizations in behavioral assessments increases the separation between Ube3am−/p+ and wild-type mouse clusters.

## Abstract

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.

We used a three-chamber social preference test for courtship vocalizations and a tail suspension test for distress vocalizations in adult wild-type (WT) and Ube3am−/p+ littermates, and quantified USV properties using the program DeepSqueak. Next, mice 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 the context of other behaviors.

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 the courtship test but mostly typical on the distress test. Including USVs in the Ube3am−/p+ mouse behavior battery increased the distance between Ube3am−/p+ and WT clusters in principal component space.

Ube3a
m−/p+ mice have difficulty producing USVs 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.