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 (Ube3amKO) 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 Ube3amKO mice paired with an unfamiliar genotype-matched female. Single housing wild type mice increased these same social behavior parameters to levels observed in Ube3amKO 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.

A placental mammal‐specific micro RNA cluster acts as a natural brake for sociability in mice

“…In addition, specific miRNAs, including miR-124 and the miR379-410 cluster, were shown to control anxiety-like behaviour [23,[27][28][29]. Intriguingly, the unusual combination of hypersocial and anxiety-like behaviour we observed in miR379-410 ko mice is present in patients suffering from two rare neurodevelopmental disorders, WBS [30] and AS [31]. The candidate disease genes of WBS and AS, LIMK1 and UBE3A, represent validated targets of miR-134 [7,22], raising the possibility that a common molecular aetiology could underlie phenotypic alterations observed in WBS, AS and miR379-410 deficiency.…”

Generation of a Novel Rat Model of Angelman Syndrome with a Complete Ube3a Gene Deletion

“…AS 129 mice had low activity making assessment difficult, while B6 AS mice had reduced exploration during the social approach testing but no significant deficits in social approach [Allensworth, Saha, Reiter, & Heck, 2011;Huang et al, 2013]. Interestingly the FVB AS mice (back-crossed into FVB) demonstrated an increase in social interactions with a novel mouse [Stoppel & Anderson, 2017]. Therefore, we examined the rats in a social approach test.…”

The sociability spectrum: evidence from reciprocal genetic copy number variations

“…The molecular mechanisms behind the sociability disruption in 15q11-13-related syndromes have been widely studied and chiefly associated with UBE3A [134,135], thought to be the main responsible for the increased risk of ASD in PWS patients [136,137]. Transgenic mice carrying an Ube3a duplication showed a dose-dependency of its gene product to sociability manifestations, in particular fact, mice with maternally-inherited Ube3a deletion displayed a prolonged preference interaction with social stimuli in the threechamber social approach task [134]. Mechanistic dissection showed that the accumulation of UBE3A in the nucleus downregulates the glutamatergic synapse organizer CBLN1, which is needed for sociability in mice, through the regulation of the activity of VGLUT2-expressing neurons in the ventral tegmental area (VTA) [138].…”