Increased rates of cerebral protein synthesis in Shank3 knockout mice: Implications for a link between synaptic...

SHANK3 is a postsynaptic scaffolding protein that plays a critical role in synaptic development and brain function. Mutations in SHANK3 are implicated in Phelan-McDermid syndrome (PMS), a neurodevelopmental disorder characterized by autistic-like behavior, delayed speech, hypotonia, and intellectual disability (ID). Moreover, mutations in SHANK3 occur in 1-2% of cases of idiopathic autism spectrum disorder (ASD). In fragile X syndrome (FXS), a syndromic form of autism, SHANK3 is one of the 842 targets of fragile X mental retardation protein (FMRP), the protein product of the silenced FMR1 gene. FXS is likely a primary disorder of the regulation of translation, whereas other syndromic forms of ASD/ID, e.g. PMS, appear to be primary disorders of synaptic structure. In this study, we asked if a knockout of the synaptic protein, Shank3, is linked to an effect on translation. Specifically, we measured the effect of Shank3 loss on rates of cerebral protein synthesis (rCPS) in vivo by means of the L-[1-¹⁴C]leucine quantitative autoradiographic method. We found that Shank3 knockout mice had significantly increased rCPS in every brain region examined. Our results suggest a link in ASD/ID between synaptic structure and regulation of translation.