AAV-mediated TBR1 supplementation ameliorates behavioral and electrophysiological abnormalities in Tbr1-haploinsufficient mice

Authors

Li, T., Jiao, Z., Wang, X., Yu, C., Qiu, Z.

Abstract

TBR1 haploinsufficiency causes a neurodevelopmental disorder associated with intellectual disability and autistic features, but the therapeutic potential of postnatal gene supplementation remains incompletely defined. Here, we evaluated adeno associated virus (AAV) mediated human TBR1 supplementation in Tbr1 haploinsufficient mice. A single retroorbital injection of AAV expressing human TBR1 under the human synapsin promoter was administered at postnatal day 3 at a dose of 2E11 vector genomes. Compared with control vector treated mutants, treated mice exhibited increased TBR1 protein abundance and TBR1, CTIP2, and parvalbumin positive cell counts in selected brain regions. Treatment improved sociability, social transmission of food preference, and buried food seeking. Electroencephalographic (EEG) recordings showed attenuation of elevated relative theta power and improved theta suppression and gamma enhancement during social interaction. However, anterior commissure abnormalities persisted, correction of other EEG abnormalities was incomplete, and sleep wake proportions showed no significant treatment improvement. These findings demonstrate that neonatal TBR1 supplementation improves selected behavioral and electrophysiological outcomes despite persistent anatomical abnormalities. They support further development of gene supplementation for TBR1 haploinsufficiency and identify social interaction associated EEG modulation as a candidate measure of treatment response.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 29 Sep 2026.

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