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

TBR1 haploinsufficiency causes a neurodevelopmental disorder associated with intellectual disability and autistic features, but the therapeutic potential of postnatal gene replacement remains incompletely defined. Here, we evaluated adeno-associated virus (AAV)-mediated human TBR1 replacement in Tbr1 -haploinsufficient mice. A single retro-orbital injection of AAV-PHP.eB expressing human TBR1 under the human synapsin promoter was administered at postnatal day 3 at a dose of 2 × 10 ¹¹ 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 replacement improves selected behavioral and electrophysiological outcomes despite persistent anatomical abnormalities. These findings support further development of gene replacement for TBR1 haploinsufficiency and highlight EEG measures as candidate biomarkers for monitoring treatment response.