Social Behavior and Gene Expression Disturbances in Mouse Models of Angelman Syndrome and Idic15 Autism

Reciprocal changes in UBE3A gene dosage cause two neurodevelopmental disorders. Maternally inherited deletions of UBE3A cause Angelman syndrome, characterized by intellectual disability, motor defects, seizures, and a pathognomonic increased social motivation. Whereas maternally inherited triplications of UBE3A as in Idic15 Autism underlie decreased sociability and increased repetitive restrictive behaviors of this disorder. Identifying the cellular compartments and neuronal subtypes where excess and loss of Ube3a impair behavior is essential to understanding and potentially treating the disorders. In Chapter 2, we show that mouse models of maternal loss of UBE3A (Ube3a-mKO, Angelman syndrome) and triplication of UBE3A (Ube3a-2x, Idic15) have opposite effects on social behavioral and cortical gene expression. Social preference and social vocalizations are reduced in Ube3a-2x and increased in Ube3a-mKO mimicking the human phenotypes. Using a nuclear localizing signal tagged Ube3a transgenic mouse (Ube3a-NLS), we show that Ube3a acts in the nucleus to impair social behavior and cortical gene expression. Many of the genes reciprocally regulated by nuclear Ube3a are part of an Autism protein-interaction network. In Chapter 3, we demonstrate Ube3a-2x mice have increased aggression, an important Autism comorbidity. In contrast, maternal loss of Ube3a reduces aggression, consistent with the gregarious, amiable nature of individuals with Angelman syndrome. We then mapped the loci where increased Ube3a increases aggression. Increased aggression was observed when Ube3a was targeted to glutamatergic and vasopressinergic but not to GABAergic or oxytocinergic neurons. In Chapter 4, we show that in mice, social behavior is downregulated by social experience via Ube3a. In wild-type mice, altering their social environment strongly regulates their social behavior: individual housing causes hypersocial whereas group housing causes hyposocial behavior. In Ube3a-2x animals, group housing caused an excessive downregulation of social behavior whereas single housing fully rescued their social behavior deficits. By contrast, in Ube3a-mKO animals, the suppressive effects of group housing on social experience was largely blocked, suggesting Ube3a is required for this process. In summary, this thesis characterizes the role of UBE3A gene dosage in regulating social and aggression behaviors and identifies the subcellular compartment and neuronal subtypes where changes in Ube3a gene dosage disturb the homeostasis of these behaviors.