Deletion of Gtf2i via Systemic Administration of AAV-PHP.eB Virus Increases Social Behavior in a Mouse Model of a Neurodevelopmental Disorder

Omer Ophir, Gilad Levy, Ela Bar, Omri Kimchi Feldhorn, May Rokach, Galit Elad Sfadia, Boaz Barak

Research output: Contribution to journalArticlepeer-review

Abstract

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 Gtf2i. Prior research indicated a strong association between pre-natal Gtf2i deletion, and the hyper-social phenotypes observed in WS, as well as myelination deficits. As most studies addressed pre-natal Gtf2i deletion in mouse models, post-natal neuronal roles of Gtf2i were unknown. To investigate the impact of post-natal deletion of neuronal Gtf2i 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 Gtf2i. This targeted deletion was performed in young mice, allowing for precise and efficient brain-wide infection leading to the exclusive removal of Gtf2i 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.

Original languageEnglish
Article number2273
JournalBiomedicines
Volume11
Issue number8
DOIs
StatePublished - Aug 2023

Keywords

  • Gtf2i
  • PHP.eB serotype
  • Williams syndrome (WS)
  • adeno-associated virus (AAV)
  • excitatory neurons
  • post-natal deletion
  • social behavior

All Science Journal Classification (ASJC) codes

  • General Biochemistry,Genetics and Molecular Biology
  • Medicine (miscellaneous)

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