Consiglio Nazionale delle Ricerche

Tipo di prodottoArticolo in rivista
TitoloImportance of Shank3 protein in regulating metabotropic glutamate receptor 5 (mGluR5) expression and signaling at synapses.
Anno di pubblicazione2011
Autore/iVerpelli C, Dvoretskova E, Vicidomini C, Rossi F, Chiappalone M, Schoen M, Di Stefano B, Mantegazza R, Broccoli V, Bockers TM, Dityatev A and Sala C
Affiliazioni autoriFrom the ?Department of Pharmacology, CNR Institute of Neuroscience, University of Milan, Milan 20129, the §Department of Neuromuscular Diseases and Neuroimmunology, Neurological Institute Foundation Carlo Besta, Milan 20133, the ¶Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genova 16163, ?Institute of Anatomy and Cell Biology, Ulm University Faculty of Medicine, Ulm 89081, and the **Division of Neuroscience, San Raffaele Scientific Institute, Milan 20132, Italy
Autori CNR e affiliazioni
  • inglese
AbstractShank3/PROSAP2 gene mutations are associated with cognitive impairment ranging from mental retardation to autism. Shank3 is a large scaffold postsynaptic density protein implicated in dendritic spines and synapse formation; however, its specific functions have not been clearly demonstrated. We have used RNAi to knockdown Shank3 expression in neuronal cultures and showed that this treatment specifically reduced the synaptic expression of the metabotropic glutamate receptor 5 (mGluR5), but did not affect the expression of other major synaptic proteins. The functional consequence of Shank3 RNAi knockdown was impaired signaling via mGluR5, as shown by reduction in ERK1/2 and CREB phosphorylation induced by stimulation with (S)-3,5-dihydroxyphenylglycine (DHPG) as the agonist of mGluR5 receptors, impaired mGluR5-dependent synaptic plasticity (DHPG-induced long-term depression), and impaired mGluR5-dependent modulation of neural network activity. We also found morphological abnormalities in the structure of synapses (spine number, width, and length) and impaired glutamatergic synaptic transmission, as shown by reduction in the frequency of miniature excitatory postsynaptic currents (mEPSC). Notably, pharmacological augmentation of mGluR5 activity using 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)-benzamide as the positive allosteric modulator of these receptors restored mGluR5-dependent signaling (DHPG-induced phosphorylation of ERK1/2) and normalized the frequency of mEPSCs in Shank3-knocked down neurons. These data demonstrate that a deficit in mGluR5-mediated intracellular signaling in Shank3 knockdown neurons can be compensated by 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)-benzamide; this raises the possibility that pharmacological augmentation of mGluR5 activity represents a possible new therapeutic approach for patients with Shank3 mutations.
Lingua abstractinglese
Altro abstract-
Lingua altro abstract-
Pagine da34839
Pagine a34850
Pagine totali-
RivistaThe Journal of biological chemistry (Print)
Attiva dal 1905
Editore: American Society for Biochemistry and Molecular Biology [etc.] - [Baltimore, etc.]
Paese di pubblicazione: Stati Uniti d'America
Lingua: inglese
ISSN: 0021-9258
Titolo chiave: The Journal of biological chemistry (Print)
Titolo proprio: The Journal of biological chemistry. (Print)
Titolo abbreviato: J. biol. chem. (Print)
Titolo alternativo: JBC (Print)
Numero volume della rivista286
Fascicolo della rivista-
Verificato da refereeSì: Internazionale
Stato della pubblicazionePublished version
Indicizzazione (in banche dati controllate)-
Parole chiaveGlutamate Receptors Ionotropic (AMPA, NMDA) Glutamate Receptors Metabotropic Receptor Regulation shRNA Synapses Dendritic Spines Mental Retardation Postsynaptic Density
Link (URL, URI)-
Titolo parallelo-
Scadenza embargo-
Data di accettazione-
Note/Altre informazioni-
Strutture CNR
  • IN — Istituto di neuroscienze
Moduli/Attività/Sottoprogetti CNR
  • ME.P02.007.001 : Farmacologia Cellulare e Molecolare delle Cellule Nervose
Progetti Europei-

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