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.
Highlights
Genetic aspects of autism spectrum disorders (ASDs) have recently been extensively explored, but environmental influences that affect ASDs have received considerably less attention
Based on the close associations among Zn, NMDA receptors (NMDARs), Shank and ASD mentioned above, we reasoned that Zn delivered to postsynaptic compartments might rescue the reduced NMDAR function and ASD-like behaviours observed in Shank2 À / À mice
We found that Shank2 À / À mice displayed reduced social interaction compared with wild-type (WT) mice, as determined by time spent exploring/sniffing the target and the social preference indices derived from exploration time (Fig. 1a–c and Supplementary Fig. 1a,d–i), consistent with previous results from untreated Shank2 À / À and WT mice45
Summary
Genetic aspects of autism spectrum disorders (ASDs) have recently been extensively explored, but environmental influences that affect ASDs have received considerably less attention. Clioquinol improves social interaction in mice haploinsufficient for the transcription factor Tbr, 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. Studies using mouse models of ASD carrying these mutations have begun to suggest possible mechanisms that may underlie the pathogenesis of ASD, namely glutamatergic dysfunction and an imbalance between excitatory and inhibitory synapses4–14 Environmental influences, such as nutrition, toxins and poisons, drugs, infection and stress, are thought to have a significant influence on psychiatric disorders. Some Zn ions enter the postsynaptic sites through calcium channels, NMDARs and calcium-permeable AMPA receptors (AMPARs), and regulate target proteins such as NMDARs and TrkB receptors through mechanisms including those involving Src family tyrosine kinases (SFKs). Zn binds to Shank2/3 and enhances their postsynaptic stabilization, promoting excitatory synapse formation and maturation
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