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

TBR1 haploinsufficiency causes a neurodevelopmental disorder characterized by intellectual disability and autistic features, but the therapeutic potential of postnatal gene supplementation has remained incompletely defined.

To address this, researchers evaluated AAV-mediated human TBR1 supplementation in Tbr1-haploinsufficient mice. A single retroorbital injection of AAV expressing human TBR1 under the human synapsin promoter was given at postnatal day 3 at a dose of 2E11 vector genomes.

Compared with control vector-treated mutants, treated mice showed increased TBR1 protein abundance and increased counts of TBR1-, CTIP2-, and parvalbumin-positive cells in selected brain regions. Treatment also improved sociability, social transmission of food preference, and buried food seeking. 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. The 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.