Restoring Shank3 in the rostral brainstem of shank3ab−/− zebrafish autism models rescues sensory deficits

• Published in: Communications biology Vol. 4; no. 1; p. 1411
• Main Authors: Kozol, Robert A., James, David M., Varela, Ivan, Sumathipala, Sureni H., Züchner, Stephan, Dallman, Julia E.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 17.12.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/51; 14; 14/19; 45; 45/70; 631/378/2629; 64; 64/116; 692/617/375/366/1373; Adaptation; Animals; Autism; Autistic Disorder - genetics; Autistic Disorder - physiopathology; Biology; Biomedical and Life Sciences; Brain; Brain mapping; Brain stem; Brain Stem - physiology; Chromosome Deletion; Chromosome Disorders - genetics; Chromosome Disorders - metabolism; Chromosomes, Human, Pair 22 - genetics; Chromosomes, Human, Pair 22 - metabolism; Danio rerio; Disease Models, Animal; Hindbrain; Information processing; Life Sciences; Light effects; Mutants; Mutation; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Sensorimotor integration; Sensory integration; Sensory stimuli; Zebrafish; Zebrafish Proteins - genetics; Zebrafish Proteins - metabolism
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-021-02920-6

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. Robert Kozol et al. developed two zebrafish Shank3 models to characterize the basis of sensorimotor deficits, which are a consistent feature in SHANK3 -deficient human patients (Phelan-McDermid Syndrome). Their results suggest that hindbrain regions require Shank3 for normal responses to light, and provide further insight toward the biology of sensory deficits in Shank3 mutants.