Hypersociability in the Angelman syndrome mouse model

Abstract

Deletions and reciprocal triplications of the human chromosomal 15q11-13 region cause two distinct neurodevelopmental disorders. Maternally-derived deletions or inactivating mutations of UBE3A, a 15q11-13 gene expressed exclusively from the maternal allele in neurons, cause Angelman syndrome, characterized by intellectual disability, motor deficits, seizures, and a characteristic increased social smiling, laughing, and eye contact. Conversely, maternally-derived triplications of 15q11-13 cause a behavioral disorder on the autism spectrum with clinical features that include decreased sociability that we recently reconstituted in mice with Ube3a alone. Based on the unique sociability features reported in Angelman syndrome and the repressed sociability observed when Ube3a gene dosage is increased, we hypothesized that mice with neuronal UBE3A loss that models Angelman syndrome would display evidence of hypersocial behavior. We report that mice with maternally-inherited Ube3a gene deletion (Ube3a^mKO) have a prolonged preference for, and interaction with, social stimuli in the three chamber social approach task. By contrast, interactions with a novel object are reduced. Further, ultrasonic vocalizations and physical contacts are increased in male and female Ube3a^mKO mice paired with an unfamiliar genotype-matched female. Single housing wild type mice increased these same social behavior parameters to levels observed in Ube3a^mKO mice where this effect was partially occluded. These results indicate sociability is repressed by social experience and the endogenous levels of UBE3A protein and suggest some social behavioral features observed in Angelman syndrome may reflect an increased social motivation.

Keywords: Angelman syndrome; Autism; Intellectual disability; Social behavior; UBE3A; Ultrasonic vocalizations.

Fig. 1

Angelman syndrome model mice are hypersocial in the three chamber test. Three chamber social preference during two consecutive five minutes trials in WT and Ube3a^mKO mice. (A) Time sniffing the social (novel mouse) or opposite (empty) chamber for female WT and p-Ube3a-mKO mice. (B) Time spent in the social, middle, or opposite chamber for female WT and p-Ube3a-mKO mice. (C) Time sniffing for female WT and m-Ube3a-mKO mice. (D) Time in zone for female WT and m-Ube3a-mKO mice. All values are mean ± SEM. **p < 0.01, ***p < 0.001.

Fig. 2

Female Angelman syndrome model mice generated increased ultrasonic vocalizations and physical contacts when paired. Female-female paired ultrasonic vocalizations [number (A) and duration (B)] and physical contacts [duration (C) and number (D)] generated by pairs of female WT or p-Ube3a-mKO mice. Female-female paired ultrasonic vocalizations [number (E) and duration (F)] and physical contacts [duration (G) and number (H)] generated by pairs of female WT or m-Ube3a-mKO mice. All values are mean ± SEM. **p < 0.01, ***p < 0.001.

Fig. 3

Angelman syndrome model mice display a reduced interest in a novel object and impaired rotorod performance. Latency (A), duration (B) and number (C) of novel object explorations for WT and p-Ube3a-mKO animals. (D) Distance moved in an open field in WT and p-Ube3a-mKO mice. Rotorod performance for WT and p-Ube3a-mKO (E) and WT and m-Ube3a-mKO (F) mice. All values are mean ± SEM. *p < 0.05, **p < 0.01, ***p < 0.001.

Fig. 4

Group housing represses three chamber social preference in wild-type but not Angelman syndrome model mice. (A) Time in zone during the second five minutes trial for WT and p-Ube3a-mKO animals single housed for six days then grouped for twenty-four hours. (B) Time in zone during the second five minutes trial for WT and m-Ube3a-mKO animals single housed for six days then grouped for twenty-four hours. All values are mean ± SEM. *p < 0.05, **p < 0.01, ***p < 0.001.

Fig. 5

Group housing strongly represses female-female paired ultrasonic vocalizations in wild-type mice; an effect attenuated in Angelman syndrome model mice. (A) Protocol for paired ultrasonic vocalizations measurements in response to housing manipulations. (B) Female-female paired ultrasonic vocalizations were measured in WT and p-Ube3a-mKO mice before and after twenty-four hours or six days of single housing. (C) The same measurements performed in WT and m-Ube3a-mKO mice. All values are mean ± SEM. *p < 0.05.