Decreased expression of ribosomal protein Rpl3 contributes to behavioral deficits caused by Shank3 deficiency

Abstract

Abstract Mutations or deletions in the SHANK3 gene have been identified in up to 1% of autism spectrum disorder cases and are considered the main cause of neuropsychiatric symptoms of Phelan McDermid syndrome (PMS). While in the absence of Shank3, synaptic dysfunctions have been extensively described, other mechanisms through which Shank3 could regulate neuronal functions have not been clearly elucidated. Here, we reported that the ribosomal protein Rpl3 was downregulated in cortex and striatum of Shank3 KO mice and in neurons differentiated from hiPSCs derived from a PMS patient. Rpl3 is essential for ribosomal biogenesis and function and its reduced expression resulted in impaired protein synthesis in Shank3 KO mice that can be rescued by restoring its expression. Furthermore, we showed that chronic treatment with VU0409551, a potent and selective mGlu5 positive allosteric modulator, rescued Rpl3 expression and the resulting reduced protein synthesis, leading to a long-lasting improvement of behavioral deficits in Shank3 KO mice. Altogether, we suggest a new role for Shank3 in modulating ribosomal function and protein synthesis, and that restoring protein synthesis could be a strategy to correct Shank3 KO related behavioral phenotypes.