title: Shank3 Is Part of a Zinc-Sensitive Signaling System That Regulates Excitatory Synaptic Strength.
abstract: 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 (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.
  
  
  
  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.
authors: Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California 94305.
authors: Magali H
authors: MH
authors: Arons
authors: Department of Physiology, University of Auckland, Auckland 92019, New Zealand.
authors: Kevin
authors: 0000-0002-8385-4786
authors: K
authors: Lee
authors: Department of Physiology, University of Auckland, Auckland 92019, New Zealand.
authors: Charlotte J
authors: CJ
authors: Thynne
authors: Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California 94305.
authors: Sally A
authors: 0000-0001-7790-4065
authors: SA
authors: Kim
authors: Institute for Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany, and.
authors: Claudia
authors: C
authors: Schob
authors: Institute for Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany, and.
authors: Stefan
authors: S
authors: Kindler
authors: Department of Physiology, University of Auckland, Auckland 92019, New Zealand, craig-curtis.garner@dzne.de jm.montgomery@auckland.ac.nz.
authors: Johanna M
authors: 0000-0002-8714-7456
authors: JM
authors: Montgomery
authors: Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California 94305, German Centers for Neurodegenerative Disorders, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany craig-curtis.garner@dzne.de jm.montgomery@auckland.ac.nz.
authors: Craig C
authors: CC
authors: Garner
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002614:Chelating Agents / Q000494:pharmacology; D002712:Chlorides / Q000494:pharmacology; D049229:Dendritic Spines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D005029:Ethylenediamines / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D005260:Female; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology; D000072233:Homer Scaffolding Proteins / Q000378:metabolism; D008297:Male; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D018408:Patch-Clamp Techniques; D038761:Photobleaching; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D018091:Receptors, AMPA / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D013569:Synapses / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D009435:Synaptic Transmission / Q000235:genetics / Q000502:physiology*; D014162:Transfection; D050598:Vesicular Glutamate Transport Protein 1 / Q000378:metabolism; D015032:Zinc / Q000378:metabolism*; D017967:Zinc Compounds / Q000494:pharmacology
chemical_list: D002614:Chelating Agents; D002712:Chlorides; D005029:Ethylenediamines; D000072233:Homer Scaffolding Proteins; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; D018091:Receptors, AMPA; C120532:Shank3 protein, rat; C493466:Slc17a7 protein, rat; D050598:Vesicular Glutamate Transport Protein 1; D017967:Zinc Compounds; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; C016837:zinc chloride; D015032:Zinc; C044387:N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine
keywords: Shank3; hippocampus; postsynaptic density; zinc