ArticleThe Journal of biological chemistry2011
Importance of Shank3 protein in regulating metabotropic glutamate receptor 5 (mGluR5) expression and signaling at synapses.
Article in The Journal of biological chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 120 papers, 1 of them a synthesis that pooled it.
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Who cites it
120 citing papers in PubMed, 1 synthesis or guideline pooled it, 207 citations in OpenAlex.
- Glutamatergic candidate genes in autism spectrum disorder: an overview.Journal of neural transmission (Vienna, Austria : 1996) · 2014Pooled it
- Is there an effect of intranasal insulin on development and behaviour in Phelan-McDermid syndrome? A randomized, double-blind, placebo-controlled trial.European journal of human genetics : EJHG · 2016Trial
- Chromosome 22q13 terminal deletion size is associated with relevant clinical features in a sample of 63 Italian patients with Phelan-McDermid syndrome.Journal of neurodevelopmental disorders · 2026Article
- Disrupted Development of the mPFC-Thalamic Circuit in Shank3Molecular psychiatry · 2026Article
- Altered Structural Plasticity Mediated by mGlu and NMDA Receptors and Impaired Cognition in a Genetic ASD Model (Shank3The Journal of neuroscience : the official journal of the Society for Neuroscience · 2026Article
- Hypersynchronous iPSC-derived SHANK2 neuronal networks are rescued by mGluR5 agonism.Stem cell reports · 2025Article
- Activity Deprivation Modulates the Shank3/Homer1/mGluR5 Signaling Pathway to Enable Synaptic Upscaling.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2025Article
- Shank3 modulates Rpl3 expression and protein synthesis via mGlu5: implications for Phelan McDermid syndrome.Molecular psychiatry · 2025Article
- Altered Neural Activity in the Mesoaccumbens Pathway Underlies Impaired Social Reward Processing in Shank3-Deficient Rats.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Deciphering the Role of Shank3 in Dendritic Morphology and Synaptic Function Across Postnatal Developmental Stages in the Shank3B KO Mouse.Neuroscience bulletin · 2025Article
- Regulation of Dendrite and Dendritic Spine Formation by TCF20.Journal of neurochemistry · 2025Article
- Clinical, developmental and serotonemia phenotyping of a sample of 70 Italian patients with Phelan-McDermid Syndrome.Journal of neurodevelopmental disorders · 2024Article
- Conditional knockout of Shank3 in the ventral CA1 by quantitative in vivo genome-editing impairs social memory in mice.Nature communications · 2024Article
- Disrupted extracellular matrix and cell cycle genes in autism-associated Shank3 deficiency are targeted by lithium.Molecular psychiatry · 2024Article
- The Shank/ProSAP N-Terminal (SPN) Domain of Shank3 Regulates Targeting to Postsynaptic Sites and Postsynaptic Signaling.Molecular neurobiology · 2024Article
- Group I and group II metabotropic glutamate receptors are upregulated in the synapses of infant rats prenatally exposed to valproic acid.Psychopharmacology · 2023Article
- Clustering of CaJournal of neurochemistry · 2023Article
- mGluR5 in hippocampal CA1 pyramidal neurons mediates stress-induced anxiety-like behavior.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2023Article
- A synaptic molecular dependency network in knockdown of autism- and schizophrenia-associated genes revealed by multiplexed imaging.Cell reports · 2023Article
- mGluR5 PAMs rescue cortical and behavioural defects in a mouse model of CDKL5 deficiency disorder.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2023Article
60 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
12 authors at 4 institutions in 2 countries.
Funding
Abstract
Shank3/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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.