Abstract
SHANK3 (also called PROSAP2) genetic haploinsufficiency is thought to be the major cause of neuropsychiatric symptoms in Phelan-McDermid syndrome (PMS). PMS is a rare genetic disorder that causes a severe form of intellectual disability (ID), expressive language delays and other autistic features. Furthermore, a significant number of SHANK3 mutations have been identified in patients with autism spectrum disorders (ASD), and SHANK3 truncating mutations are associated with moderate to profound ID. The Shank3 protein is a scaffold protein that is located in the postsynaptic density (PSD) of excitatory synapses and is crucial for synapse development and plasticity. In this study, we investigated the molecular mechanisms associated with the ASD-like behaviors observed in Shank3Δ11−/− mice, in which exon 11 has been deleted. Our results indicate that Shank3 is essential to mediating metabotropic glutamate receptor 5 (mGlu5)-receptor signaling by recruiting Homer1b/c to the PSD, specifically in the striatum and cortex. Moreover, augmenting mGlu5-receptor activity by administering 3-Cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide ameliorated the functional and behavioral defects that were observed in Shank3Δ11−/− mice, suggesting that pharmaceutical treatments that increase mGlu5 activity may represent a new approach for treating patients that are affected by PMS and SHANK3 mutations.
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Acknowledgements
This work was supported by the Comitato Telethon Fondazione Onlus (grant no. GGP13187 to CS and GGP11095 to CS and MG), Italian Institute of Technology (seed grant to CS), Foundation Jérôme Lejeune (to CV) and the Fondazione CARIPLO (project number 2012-0593 to CS and 2013-0879 to CV). TMB received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement number 115300, the resources of which are composed of a financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013) and a generous contribution from the EFPIA companies. MJS was supported by Baustein 3.2 of Ulm University (L.SBN.0081) and by the DAAD (PROCOPE 57049403).
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Vicidomini, C., Ponzoni, L., Lim, D. et al. Pharmacological enhancement of mGlu5 receptors rescues behavioral deficits in SHANK3 knock-out mice. Mol Psychiatry 22, 689–702 (2017). https://doi.org/10.1038/mp.2016.30
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DOI: https://doi.org/10.1038/mp.2016.30
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