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

Paolo Calabresi, 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, T. M. Boeckers, C. Sala, C. Verpelli

Risultato della ricerca: Contributo in rivistaArticolo in rivista

59 Citazioni (Scopus)

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.
Lingua originaleEnglish
pagine (da-a)689-702
Numero di pagine14
RivistaMolecular Psychiatry
Volume22
DOI
Stato di pubblicazionePubblicato - 2017

Keywords

  • Animals
  • Autism Spectrum Disorder
  • Behavior, Animal
  • Benzamides
  • Chromosome Deletion
  • Chromosome Disorders
  • Chromosomes, Human, Pair 22
  • Corpus Striatum
  • Exons
  • Hippocampus
  • Homer Scaffolding Proteins
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred DBA
  • Mice, Knockout
  • Microfilament Proteins
  • Nerve Tissue Proteins
  • Neurons
  • Post-Synaptic Density
  • Pyrazoles
  • Receptor, Metabotropic Glutamate 5
  • Signal Transduction
  • Synaptic Transmission

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