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Trans-synaptic zinc mobilization improves social interaction in two mouse models of autism through NMDAR activation

Author

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  • Eun-Jae Lee

    (Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology
    Center for Synaptic Brain Dysfunctions, Institute for Basic Science (IBS))

  • Hyejin Lee

    (Center for Synaptic Brain Dysfunctions, Institute for Basic Science (IBS)
    Korea Advanced Institute of Science and Technology)

  • Tzyy-Nan Huang

    (Institute of Molecular Biology, Academia Sinica)

  • Changuk Chung

    (Center for Synaptic Brain Dysfunctions, Institute for Basic Science (IBS)
    Korea Advanced Institute of Science and Technology)

  • Wangyong Shin

    (Center for Synaptic Brain Dysfunctions, Institute for Basic Science (IBS)
    Korea Advanced Institute of Science and Technology)

  • Kyungdeok Kim

    (Center for Synaptic Brain Dysfunctions, Institute for Basic Science (IBS)
    Korea Advanced Institute of Science and Technology)

  • Jae-Young Koh

    (Neural Injury Research Lab, University of Ulsan College of Medicine
    Asan Institute for Life Science, University of Ulsan College of Medicine
    University of Ulsan College of Medicine)

  • Yi-Ping Hsueh

    (Institute of Molecular Biology, Academia Sinica)

  • Eunjoon Kim

    (Center for Synaptic Brain Dysfunctions, Institute for Basic Science (IBS)
    Korea Advanced Institute of Science and Technology)

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.

Suggested Citation

  • Eun-Jae Lee & Hyejin Lee & Tzyy-Nan Huang & Changuk Chung & Wangyong Shin & Kyungdeok Kim & Jae-Young Koh & Yi-Ping Hsueh & Eunjoon Kim, 2015. "Trans-synaptic zinc mobilization improves social interaction in two mouse models of autism through NMDAR activation," Nature Communications, Nature, vol. 6(1), pages 1-13, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms8168
    DOI: 10.1038/ncomms8168
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    Cited by:

    1. Pu-Yun Shih & Yu-Lun Fang & Sahana Shankar & Sue-Ping Lee & Hsiao-Tang Hu & Hsin Chen & Ting-Fang Wang & Kuo-Chiang Hsia & Yi-Ping Hsueh, 2022. "Phase separation and zinc-induced transition modulate synaptic distribution and association of autism-linked CTTNBP2 and SHANK3," Nature Communications, Nature, vol. 13(1), pages 1-20, December.

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