title: Pharmacological enhancement of mGlu5 receptors rescues behavioral deficits in SHANK3 knock-out mice.
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.
authors.affiliation: CNR Neuroscience Institute, Milan, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Vicidomini
authors.affiliation: BIOMETRA University of Milan, Milan, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Ponzoni
authors.affiliation: Department of Pharmaceutical Sciences, Università degli Studi del Piemonte Orientale "Amedeo Avogadro", Novara, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Lim
authors.affiliation: Institute for Anatomy and Cell Biology, Ulm University, Ulm, Germany.|Department of Neurology, Ulm University, Ulm, Germany.
authors.forename: M J
authors.initials: MJ
authors.lastname: Schmeisser
authors.affiliation: Institute for Anatomy and Cell Biology, Ulm University, Ulm, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Reim
authors.affiliation: Department of Neuroscience, University of Turin, Turin, Italy.
authors.forename: N
authors.initials: N
authors.lastname: Morello
authors.affiliation: CNR Neuroscience Institute, Milan, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Orellana
authors.affiliation: Department of Experimental Medicine, University of Perugia, Perugia, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Tozzi
authors.affiliation: Department of Medicine, University of Perugia and Clinica Neurologica, Santa Maria della Misericordia Hospital, Perugia, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Durante
authors.affiliation: U.O. of Neurophysiopathology and Diagnostic Epileptology, Foundation Istituto di Ricerca e Cura a Carattere Scientifico Neurological Institute Carlo Besta, Milan, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Scalmani
authors.affiliation: Institute of Molecular and Cellular Pharmacology, Laboratory of Excellence Ion Channel Science and Therapeutics, CNRS UMR7275 and University of Nice-Sophia Antipolis, Valbonne, France.
authors.forename: M
authors.initials: M
authors.lastname: Mantegazza
authors.affiliation: Department of Pharmaceutical Sciences, Università degli Studi del Piemonte Orientale "Amedeo Avogadro", Novara, Italy.
authors.forename: A A
authors.initials: AA
authors.lastname: Genazzani
authors.affiliation: Department of Neurology, Ulm University, Ulm, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Giustetto
authors.affiliation: CNR Neuroscience Institute, Milan, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Sala
authors.affiliation: Department of Medicine, University of Perugia and Clinica Neurologica, Santa Maria della Misericordia Hospital, Perugia, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Calabresi
authors.affiliation: Institute for Anatomy and Cell Biology, Ulm University, Ulm, Germany.
authors.forename: T M
authors.initials: TM
authors.lastname: Boeckers
authors.affiliation: CNR Neuroscience Institute, Milan, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Sala
authors.affiliation: CNR Neuroscience Institute, Milan, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Verpelli
mesh_terms: D000818:Animals; D000067877:Autism Spectrum Disorder / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism*; D001522:Behavior, Animal / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology*; D002872:Chromosome Deletion; D025063:Chromosome Disorders / Q000235:genetics / Q000378:metabolism; D002892:Chromosomes, Human, Pair 22 / Q000235:genetics / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D005091:Exons; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D000072233:Homer Scaffolding Proteins / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D057907:Post-Synaptic Density / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D064529:Receptor, Metabotropic Glutamate 5 / Q000378:metabolism*; D015398:Signal Transduction; D009435:Synaptic Transmission
chemical_list: C494553:3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide; D001549:Benzamides; D000072233:Homer Scaffolding Proteins; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D011720:Pyrazoles; D064529:Receptor, Metabotropic Glutamate 5; C492356:Shank3 protein, mouse