Shank3 Is Part of a Zinc-Sensitive Signaling System That Regulates Excitatory Synaptic Strength
| Autor: | Stefan Kindler, Charlotte J. Thynne, Craig C. Garner, Kevin Lee, Johanna M. Montgomery, Claudia Schob, Magali H. Arons, Sally A. Kim |
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| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine Patch-Clamp Techniques Nonsynaptic plasticity drug effects [Synapses] enhanced green fluorescent protein Hippocampus Synaptic Transmission pharmacology [Chelating Agents] genetics [Excitatory Postsynaptic Potentials] 0302 clinical medicine Homer Scaffolding Proteins Slc17a7 protein rat RNA Small Interfering Cells Cultured genetics [Nerve Tissue Proteins] Chelating Agents Neurons ultrastructure [Neurons] Photobleaching General Neuroscience Articles physiology [Neurons] Ethylenediamines metabolism [Zinc] genetics [Synapses] Zinc pharmacology [Chlorides] Excitatory postsynaptic potential Female pharmacology [Ethylenediamines] Signal Transduction drug effects [Excitatory Postsynaptic Potentials] genetics [Synaptic Transmission] Dendritic Spines metabolism [Homer Scaffolding Proteins] Green Fluorescent Proteins N N N' N'-tetrakis(2-pyridylmethyl)ethylenediamine genetics [Mutation] Nerve Tissue Proteins Neurotransmission Biology genetics [Signal Transduction] Transfection zinc chloride Inhibitory postsynaptic potential 03 medical and health sciences pharmacology [Zinc Compounds] Chlorides metabolism [Vesicular Glutamate Transport Protein 1] Synaptic augmentation physiology [Signal Transduction] Metaplasticity Animals genetics [Green Fluorescent Proteins] drug effects [Neurons] ddc:610 Receptors AMPA metabolism [Nerve Tissue Proteins] Dose-Response Relationship Drug metabolism [Receptors AMPA] Excitatory Postsynaptic Potentials pharmacology [RNA Small Interfering] Shank3 protein rat Embryo Mammalian Rats 030104 developmental biology metabolism [Dendritic Spines] physiology [Synaptic Transmission] Zinc Compounds metabolism [Green Fluorescent Proteins] cytology [Hippocampus] Mutation Synapses Vesicular Glutamate Transport Protein 1 Synaptic plasticity physiology [Synapses] Neuroscience Postsynaptic density 030217 neurology & neurosurgery |
| Zdroj: | The journal of neuroscience 36(35), 9124-9134 (2016). doi:10.1523/JNEUROSCI.0116-16.2016 |
| ISSN: | 1529-2401 0270-6474 |
| DOI: | 10.1523/jneurosci.0116-16.2016 |
| Popis: | Shank3 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 (Shank3R87C) 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. |
| Databáze: | OpenAIRE |
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