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

Nat Commun. 2015 May 18;6:7168. doi: 10.1038/ncomms8168.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amygdala / metabolism
  • Animals
  • Autistic Disorder / physiopathology*
  • Behavior, Animal
  • Chelating Agents / chemistry
  • Clioquinol / chemistry
  • Crosses, Genetic
  • DNA-Binding Proteins / metabolism
  • Dendrites / metabolism
  • Disease Models, Animal
  • Electrophysiology
  • Female
  • Haploinsufficiency
  • Hippocampus / metabolism
  • Ionophores / chemistry
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Nerve Tissue Proteins / metabolism
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Social Behavior
  • Synapses / metabolism*
  • Synaptic Transmission / physiology
  • Zinc / chemistry*
  • src-Family Kinases / metabolism

Substances

  • Chelating Agents
  • DNA-Binding Proteins
  • Ionophores
  • Nerve Tissue Proteins
  • Receptors, N-Methyl-D-Aspartate
  • Tbr1 protein, mouse
  • Clioquinol
  • src-Family Kinases
  • Zinc