title: Trans-synaptic zinc mobilization improves social interaction in two mouse models of autism through NMDAR activation.
abstract: Genetic aspects of autism spectrum disorders (ASDs) have recently been extensively explored, but environmental influences that affect ASDs have received considerably less attention. Zinc (Zn) is a nutritional factor implicated in ASDs, but evidence for a strong association and linking mechanism is largely lacking. Here we report that trans-synaptic Zn mobilization rapidly rescues social interaction in two independent mouse models of ASD. In mice lacking Shank2, an excitatory postsynaptic scaffolding protein, postsynaptic Zn elevation induced by clioquinol (a Zn chelator and ionophore) improves social interaction. Postsynaptic Zn is mainly derived from presynaptic pools and activates NMDA receptors (NMDARs) through postsynaptic activation of the tyrosine kinase Src. Clioquinol also improves social interaction in mice haploinsufficient for the transcription factor Tbr1, which accompanies NMDAR activation in the amygdala. These results suggest that trans-synaptic Zn mobilization induced by clioquinol rescues social deficits in mouse models of ASD through postsynaptic Src and NMDAR activation.
authors.affiliation: Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea.|Center for Synaptic Brain Dysfunctions, Institute for Basic Science (IBS), Daejeon 305-701, Korea.
authors.forename: Eun-Jae
authors.initials: EJ
authors.lastname: Lee
authors.affiliation: Center for Synaptic Brain Dysfunctions, Institute for Basic Science (IBS), Daejeon 305-701, Korea.|Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea.
authors.forename: Hyejin
authors.initials: H
authors.lastname: Lee
authors.affiliation: Institute of Molecular Biology, Academia Sinica, Taipei 115, Taiwan.
authors.forename: Tzyy-Nan
authors.initials: TN
authors.lastname: Huang
authors.affiliation: Center for Synaptic Brain Dysfunctions, Institute for Basic Science (IBS), Daejeon 305-701, Korea.|Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea.
authors.forename: Changuk
authors.initials: C
authors.lastname: Chung
authors.affiliation: Center for Synaptic Brain Dysfunctions, Institute for Basic Science (IBS), Daejeon 305-701, Korea.|Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea.
authors.forename: Wangyong
authors.initials: W
authors.lastname: Shin
authors.affiliation: Center for Synaptic Brain Dysfunctions, Institute for Basic Science (IBS), Daejeon 305-701, Korea.|Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea.
authors.forename: Kyungdeok
authors.initials: K
authors.lastname: Kim
authors.affiliation: Neural Injury Research Lab, University of Ulsan College of Medicine, Seoul 138-736, Korea.|Asan Institute for Life Science, University of Ulsan College of Medicine, Seoul 138-736, Korea.|Department of Neurology, University of Ulsan College of Medicine, Seoul 138-736, Korea.
authors.forename: Jae-Young
authors.initials: JY
authors.lastname: Koh
authors.affiliation: Institute of Molecular Biology, Academia Sinica, Taipei 115, Taiwan.
authors.forename: Yi-Ping
authors.initials: YP
authors.lastname: Hsueh
authors.affiliation: Center for Synaptic Brain Dysfunctions, Institute for Basic Science (IBS), Daejeon 305-701, Korea.|Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea.
authors.forename: Eunjoon
authors.initials: E
authors.lastname: Kim
mesh_terms: D000679:Amygdala / Q000378:metabolism; D000818:Animals; D001321:Autistic Disorder / Q000503:physiopathology*; D001522:Behavior, Animal; D002614:Chelating Agents / Q000737:chemistry; D007464:Clioquinol / Q000737:chemistry; D003433:Crosses, Genetic; D004268:DNA-Binding Proteins / Q000378:metabolism; D003712:Dendrites / Q000378:metabolism; D004195:Disease Models, Animal; D004594:Electrophysiology; D005260:Female; D057895:Haploinsufficiency; D006624:Hippocampus / Q000378:metabolism; D007476:Ionophores / Q000737:chemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D012919:Social Behavior; D013569:Synapses / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology; D020825:T-Box Domain Proteins; D015032:Zinc / Q000737:chemistry*; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D002614:Chelating Agents; D004268:DNA-Binding Proteins; D007476:Ionophores; D009419:Nerve Tissue Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D020825:T-Box Domain Proteins; C492271:Tbr1 protein, mouse; D007464:Clioquinol; D019061:src-Family Kinases; D015032:Zinc