Pharmacological enhancement of mGlu5 receptors rescues behavioral deficits in SHANK3 knock-out mice

C. Vicidomini, L. Ponzoni, D. Lim, M. J. Schmeisser, D. Reim, N. Morello, D. Orellana, A. Tozzi, V. Durante, P. Scalmani, M. Mantegazza, A. A. Genazzani, M. Giustetto, M. Sala, P. Calabresi, T. M. Boeckers, C. Sala, C. Verpelli

Research output: Contribution to journalArticlepeer-review


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.Molecular Psychiatry advance online publication, 29 March 2016; doi:10.1038/mp.2016.30.

Original languageEnglish
JournalMolecular Psychiatry
Publication statusAccepted/In press - Mar 29 2016

ASJC Scopus subject areas

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience


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