ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2016
Shank3 Is Part of a Zinc-Sensitive Signaling System That Regulates Excitatory Synaptic Strength.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed, 61 citations in OpenAlex.
- The role of zinc homeostasis in major depressive disorder: heterogeneous pathological mechanisms and therapeutic implications.Annals of medicine · 2026Review
- Unraveling the Genetic and Molecular Architecture of Autism Spectrum Disorder: Implications for Clinical Genetics and Genomic Diagnostics.International journal of molecular sciences · 2026Review
- Gut-Brain Axis: Understanding the Interlink Between Alterations in the Gut Microbiota and Autism Spectrum Disorder.Cureus · 2025Review
- Effect of dietary zinc supplementation on the gastrointestinal microbiome and host gene expression in theFrontiers in microbiology · 2025Article
- Differential effectiveness of dietary zinc supplementation with autism-related behaviours inPhilosophical transactions of the Royal Society of London. Series B, Biological sciences · 2024Article
- Trans-synaptic Association of Vesicular Zinc Transporter 3 and Shank3 Supports Synapse-Specific Dendritic Spine Structure and Function in the Mouse Auditory Cortex.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2024Article
- nArgBP2 together with GKAP and SHANK3 forms a dynamic layered structure.Frontiers in cellular neuroscience · 2024Article
- Neurodevelopmental Consequences of Dietary Zinc Deficiency: A Status Report.Biological trace element research · 2023Review
- Schizophrenia as metabolic disease. What are the causes?Metabolic brain disease · 2023Review
- The Role of Zinc and NMDA Receptors in Autism Spectrum Disorders.Pharmaceuticals (Basel, Switzerland) · 2022Review
- Intracellular zinc signaling influences NMDA receptor function by enhancing the interaction of ZnT1 with GluN2A.Neuroscience letters · 2022Article
- Postsynaptic Proteins at Excitatory Synapses in the Brain-Relationship with Depressive Disorders.International journal of molecular sciences · 2022Review
- Neuronal signalling of zinc: from detection and modulation to function.Open biology · 2022Review
- Neuromotor Development in theBrain sciences · 2022Article
- Prenatal Zinc Deficient Mice as a Model for Autism Spectrum Disorders.International journal of molecular sciences · 2022Review
- Dietary zinc supplementation rescues fear-based learning and synaptic function in the Tbr1Molecular autism · 2022Article
- Utilizing Genomically Targeted Molecular Data to Improve Patient-Specific Outcomes in Autism Spectrum Disorder.International journal of molecular sciences · 2022Article
- Lack of Vesicular Zinc Does Not Affect the Behavioral Phenotype of Polyinosinic:Polycytidylic Acid-Induced Maternal Immune Activation Mice.Frontiers in behavioral neuroscience · 2022Article
- In vitro zinc supplementation alters synaptic deficits caused by autism spectrum disorder-associated Shank2 point mutations in hippocampal neurons.Molecular brain · 2021Article
- The Function and Regulation of Zinc in the Brain.Neuroscience · 2021Review
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Authors and funding
8 authors at 3 institutions in 3 countries.
Funding
Abstract
unlabelledShank3 is a multidomain scaffold protein localized to the postsynaptic density of excitatory synapses. Functional studies in vivo and in vitro support the concept that Shank3 is critical for synaptic plasticity and the trans-synaptic coupling between the reliability of presynaptic neurotransmitter release and postsynaptic responsiveness. However, how Shank3 regulates synaptic strength remains unclear. The C terminus of Shank3 contains a sterile alpha motif (SAM) domain that is essential for its postsynaptic localization and also binds zinc, thus raising the possibility that changing zinc levels modulate Shank3 function in dendritic spines. In support of this hypothesis, we find that zinc is a potent regulator of Shank3 activation and dynamics in rat hippocampal neurons. Moreover, we show that zinc modulation of synaptic transmission is Shank3 dependent. Interestingly, an autism spectrum disorder (ASD)-associated variant of Shank3 (Shank3(R87C)) retains its zinc sensitivity and supports zinc-dependent activation of AMPAR-mediated synaptic transmission. However, elevated zinc was unable to rescue defects in trans-synaptic signaling caused by the R87C mutation, implying that trans-synaptic increases in neurotransmitter release are not necessary for the postsynaptic effects of zinc. Together, these data suggest that Shank3 is a key component of a zinc-sensitive signaling system, regulating synaptic strength that may be impaired in ASD. SIGNIFICANCE STATEMENT: Shank3 is a postsynaptic protein associated with neurodevelopmental disorders such as autism and schizophrenia. In this study, we show that Shank3 is a key component of a zinc-sensitive signaling system that regulates excitatory synaptic transmission. Intriguingly, an autism-associated mutation in Shank3 partially impairs this signaling system. Therefore, perturbation of zinc homeostasis may impair, not only synaptic functionality and plasticity, but also may lead to cognitive and behavioral abnormalities seen in patients with psychiatric disorders.
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Registered trials
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