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.

Automated summary

This study reveals that dysfunction of GABAergic circuits, which are associated with neurodevelopmental disorders, is influenced by genetic predispositions. Using in vivo imaging in developing mice, the researchers found that the Gabrb3 gene, strongly associated with ASD and AS, plays a crucial role in the inhibitory function of contralaterally projecting pyramidal neurons. The deletion of Gabrb3 leads to a decrease in GABAergic synapses, increased network synchrony, and enhanced functional connectivity in contralateral-pyramidal neuron subtypes.