Gabrb3 is required for the functional integration of pyramidal neuron subtypes in the somatosensory cortex

Dysfunction of gamma-aminobutyric acid (GABA)ergic circuits is strongly associated with neurodevelop-mental disorders. However, it is unclear how genetic predispositions impact circuit assembly. Using in vivo two-photon and widefield calcium imaging in developing mice, we show that Gabrb3, a gene strongly asso-ciated with autism spectrum disorder (ASD) and Angelman syndrome (AS), is enriched in contralaterally pro-jecting pyramidal neurons and is required for inhibitory function. We report that Gabrb3 ablation leads to a developmental decrease in GABAergic synapses, increased local network synchrony, and long-lasting enhancement in functional connectivity of contralateral-but not ipsilateral-pyramidal neuron subtypes. In addition, Gabrb3 deletion leads to increased cortical response to tactile stimulation at neonatal stages. Us-ing human transcriptomics and neuroimaging datasets from ASD subjects, we show that the spatial distribu-tion of GABRB3 expression correlates with atypical connectivity in these subjects. Our studies reveal a requirement for Gabrb3 during the emergence of interhemispheric circuits for sensory processing.