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

Eun-Jae Lee, Hyejin Lee, Tzyy-Nan Huang, Changuk Chung, Wangyong Shin, Kyungdeok Kim, Jae-Young Koh, Yi-Ping Hsueh () and Eunjoon Kim ()
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Eun-Jae Lee: Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology
Hyejin Lee: Center for Synaptic Brain Dysfunctions, Institute for Basic Science (IBS)
Tzyy-Nan Huang: Institute of Molecular Biology, Academia Sinica
Changuk Chung: Center for Synaptic Brain Dysfunctions, Institute for Basic Science (IBS)
Wangyong Shin: Center for Synaptic Brain Dysfunctions, Institute for Basic Science (IBS)
Kyungdeok Kim: Center for Synaptic Brain Dysfunctions, Institute for Basic Science (IBS)
Jae-Young Koh: Neural Injury Research Lab, 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)

Nature Communications, 2015, vol. 6, issue 1, 1-13

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms8168

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