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

• Published in: Neuron (Cambridge, Mass.) Vol. 111; no. 2; pp. 256 - 274.e10
• Main Authors: Babij, Rachel, Ferrer, Camilo, Donatelle, Alexander, Wacks, Sam, Buch, Amanda M., Niemeyer, James E., Ma, Hongtao, Duan, Zhe Ran S., Fetcho, Robert N., Che, Alicia, Otsuka, Takumi, Schwartz, Theodore H., Huang, Ben S., Liston, Conor, De Marco García, Natalia V.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 18.01.2023
• Subjects: Angelman; Animals; Autism Spectrum Disorder - genetics; callosal projections; corpus callosum; GABA; GABRB3; Humans; interhemispheric connectivity; Mice; network synchrony; projection neurons; Pyramidal Cells - physiology; pyramidal neurons; Receptors, GABA-A - genetics; Somatosensory Cortex; Synapses; Touch; GABRB3; callosal projections; projection neurons; network synchrony; Angelman; pyramidal neurons; GABA; corpus callosum; interhemispheric connectivity
• ISSN: 0896-6273; 1097-4199; 1097-4199
• DOI: 10.1016/j.neuron.2022.10.037

Dysfunction of gamma-aminobutyric acid (GABA)ergic circuits is strongly associated with neurodevelopmental 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 associated with autism spectrum disorder (ASD) and Angelman syndrome (AS), is enriched in contralaterally projecting 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. Using human transcriptomics and neuroimaging datasets from ASD subjects, we show that the spatial distribution 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. [Display omitted] •Gabrb3 is necessary for cortical network desynchronization in murine S1•GABAergic disruption results in enhanced contralateral, but not ipsilateral, connectivity•Gabrb3 ablation leads to increased whisker-dependent responses during mouse development•Spatial pattern of human GABRB3 expression correlates with atypical connectivity in ASD Babij, Ferrer, et al. use mouse genetics and in vivo imaging to show that Gabrb3 is required for the developmental decorrelation of cortical networks. Gabrb3 removal leads to enhanced contralateral connectivity and hypersensitivity to tactile stimuli. In addition, GABRB3 expression is spatially correlated with atypical connectivity in ASD human subjects.