ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2013
Shank3 deficiency induces NMDA receptor hypofunction via an actin-dependent mechanism.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 78 papers, 3 of them syntheses that pooled it.
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Who cites it
78 citing papers in PubMed, 3 syntheses or guidelines pooled it, 120 citations in OpenAlex.
- Genetics of catatonia: a systematic review of case reports and a gene pathway analysis.European psychiatry : the journal of the Association of European Psychiatrists · 2025Pooled it
- Genetic variability in scaffolding proteins and risk for schizophrenia and autism-spectrum disorders: a systematic review.Journal of psychiatry & neuroscience : JPN · 2018Pooled it
- Glutamatergic candidate genes in autism spectrum disorder: an overview.Journal of neural transmission (Vienna, Austria : 1996) · 2014Pooled it
- Glycine-modulating Slc6a20a-ASO restores NMDA receptor function in SHANK2 and SHANK3-mutant mice and cortical organoids.Nature communications · 2026Article
- Disrupted Development of the mPFC-Thalamic Circuit in Shank3Molecular psychiatry · 2026Article
- Evaluating Chronic Sex-Specific Changes in Glutamatergic Signaling Markers Following Traumatic Brain Injury.International journal of molecular sciences · 2026Article
- Extracellular vesicles from stem cells rescue cellular phenotypes and behavioral deficits in SHANK3-associated ASD neuronal and mouse models.Cell death & disease · 2026Article
- GluN2B-specific NMDAR positive allosteric modulation reverses cognitive and behavioral abnormalities inScience advances · 2026Article
- SHANK3 Deficiency in AgRP Neurons Inhibits Diet-Induced Obesity by Activating p38α.Neuroscience bulletin · 2026Article
- Synaptic Deficits in Adnp-Mutant Mice Are Ameliorated by Histone Demethylase LSD1 Inhibition.Autism research : official journal of the International Society for Autism Research · 2025Article
- Multi-level profiling of the Fmr1 KO rat unveils altered behavioral traits along with aberrant glutamatergic function.Translational psychiatry · 2024Article
- Neurodevelopmental Consequences of Dietary Zinc Deficiency: A Status Report.Biological trace element research · 2023Review
- Deficits in integrative NMDA receptors caused by Grin1 disruption can be rescued in adulthood.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2023Article
- Clinical profiling of MRD48 and functional characterization of two novel pathogenic RAC1 variants.European journal of human genetics : EJHG · 2023Review
- Genetics of mirror movements identifies a multifunctional complex required for Netrin-1 guidance and lateralization of motor control.Science advances · 2023Article
- Neuroanatomical changes of ionotropic glutamatergic and GABAergic receptor densities in male mice modeling idiopathic and syndromic autism spectrum disorder.Frontiers in psychiatry · 2023Article
- Targeting Shank3 deficiency and paresthesia in autism spectrum disorder: A brief review.Frontiers in molecular neuroscience · 2023Review
- Histone Deacetylase Inhibition Restores Behavioral and Synaptic Function in a Mouse Model of 16p11.2 Deletion.The international journal of neuropsychopharmacology · 2022Article
- Postsynaptic Proteins at Excitatory Synapses in the Brain-Relationship with Depressive Disorders.International journal of molecular sciences · 2022Review
- From bench to bedside: The mGluR5 system in people with and without Autism Spectrum Disorder and animal model systems.Translational psychiatry · 2022Article
18 more citing papers are in PubMed but not listed here.
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Authors and funding
7 authors at 2 institutions in 2 countries.
Funding
Abstract
Shank3, which encodes a scaffolding protein at glutamatergic synapses, is a genetic risk factor for autism. In this study, we examined the impact of Shank3 deficiency on the NMDA-type glutamate receptor, a key player in cognition and mental illnesses. We found that knockdown of Shank3 with a small interfering RNA (siRNA) caused a significant reduction of NMDAR-mediated ionic or synaptic current, as well as the surface expression of NR1 subunits, in rat cortical cultures. The effect of Shank3 siRNA on NMDAR currents was blocked by an actin stabilizer, and was occluded by an actin destabilizer, suggesting the involvement of actin cytoskeleton. Since actin dynamics is regulated by the GTPase Rac1 and downstream effector p21-activated kinase (PAK), we further examined Shank3 regulation of NMDARs when Rac1 or PAK was manipulated. We found that the reducing effect of Shank3 siRNA on NMDAR currents was mimicked and occluded by specific inhibitors for Rac1 or PAK, and was blocked by constitutively active Rac1 or PAK. Immunocytochemical data showed a strong reduction of F-actin clusters after Shank3 knockdown, which was occluded by a PAK inhibitor. Inhibiting cofilin, the primary downstream target of PAK and a major actin depolymerizing factor, prevented Shank3 siRNA from reducing NMDAR currents and F-actin clusters. Together, these results suggest that Shank3 deficiency induces NMDAR hypofunction by interfering with the Rac1/PAK/cofilin/actin signaling, leading to the loss of NMDAR membrane delivery or stability. It provides a potential mechanism for the role of Shank3 in cognitive deficit in autism.
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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.