People with Phelan-McDermid Syndrome, caused by mutations in the SHANK3 gene, commonly exhibit reduced responses to sensory stimuli; yet the changes in brain-wide activity that link these symptoms to mutations in the shank3 gene remain unknown. Here we quantify movement in response to sudden darkness in larvae of two shank3 zebrafish mutant models and show that both models exhibit dampened responses to this stimulus. Using brain-wide activity mapping, we find that shank3−/− light-sensing brain regions show normal levels of activity while sensorimotor integration and motor regions are less active. Specifically restoring Shank3 function in a sensorimotor nucleus of the rostral brainstem enables the shank3−/− model to respond like wild-type. In sum, we find that reduced sensory responsiveness in shank3−/− models is associated with reduced activity in sensory processing brain regions and can be rescued by restoring Shank3 function in the rostral brainstem. These studies highlight the importance of Shank3 function in the rostral brainstem for integrating sensory inputs to generate behavioral adaptations to changing sensory stimuli.

People with Phelan-McDermid Syndrome, caused by mutations in the SHANK3 gene, commonly present with symptoms of sensory hyporeactivity. To investigate how shank3 mutations impact brain circuits and contribute to sensory hyporeactivity, we generated two shank3 zebrafish mutant models. These shank3 mutant models both exhibit hyporeactivity to visual stimuli. Using whole-brain activity mapping, we show that light receptive brain nuclei show normal levels of activity while sensorimotor integration and motor regions are less active in shank3-/- mutants. Specifically rescuing Shank3 in a sensorimotor nucleus of the rostral brainstem is sufficient to rescue shank3-/- mutant hyporeactivity. In summary, reduced sensory responsiveness in shank3-/- mutant is associated with reduced activity across the brain and can be rescued by restoring Shank3 function in the rostral brainstem.