Deletion of via Systemic Administration of AAV-PHP.eB Virus Increases Social Behavior in a Mouse Model of a Neurodevelopmental Disorder.

Williams syndrome (WS) is a neurodevelopmental disorder characterized by distinctive cognitive and personality profiles which also impacts various physiological systems. The syndrome arises from the deletion of about 25 genes located on chromosome 7q11.23, including . Prior research indicated a strong association between pre-natal deletion, and the hyper-social phenotypes observed in WS, as well as myelination deficits. As most studies addressed pre-natal deletion in mouse models, post-natal neuronal roles of were unknown. To investigate the impact of post-natal deletion of neuronal on hyper-sociability, we intravenously injected an AAV-PHP.eB virus expressing Cre-recombinase under the control of αCaMKII, a promoter in a mouse model with floxed . This targeted deletion was performed in young mice, allowing for precise and efficient brain-wide infection leading to the exclusive removal of from excitatory neurons. As a result of such gene deletion, the mice displayed hyper-sociability, increased anxiety, impaired cognition, and hyper-mobility, relative to controls. These findings highlight the potential of systemic viral manipulation as a gene-editing technique to modulate behavior-regulating genes during the post-natal stage, thus presenting novel therapeutic approaches for addressing neurodevelopmental dysfunction.