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

ABSTRACT: 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 mutants 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. Altered sensory processing is a pervasive but poorly understood symptom in individuals with autism spectrum disorders (ASD)1. Sensory symptoms manifest as muted or excessive responses to light, sound, and/or touch. Because of variability in both the presence and presentation of sensory symptoms, gaining a mechanistic understanding of these sensory processing deficits remains a challenge. In contrast to ASD as a whole, genetically defined forms of ASD share similar sensory deficits. For instance, individuals with Phelan McDermid Syndrome (PMS), a syndromic form of ASD, show low sensitivity to pain and reduced responses to auditory and visual stimuli 2, 3. PMS is caused by the loss of function of one copy of the SHANK3 gene, due to either terminal deletions of chromosome 22 4 or SHANK3 point mutations 2. Here we identify the neurobiological basis of sensory hyporeactivity in shank3 loss-of-function zebrafish models of PMS.

ORGANISM(S): Danio rerio (zebrafish)

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PROVIDER: S-BSST741 | biostudies-other |

REPOSITORIES: biostudies-other