Abstract
Autism Spectrum Disorders (ASD) are characterised by deficits in social interactions and repetitive behaviours. Multiple ASD-associated mutations have been identified in the Shank family of proteins that play a critical role in the structure and plasticity of glutamatergic synapses, leading to impaired synapse function and the presentation of ASD-associated behavioural deficits in mice. Shank proteins are highly regulated by zinc, where zinc binds the Shank SAM domain to drive synaptic protein recruitment and synaptic maturation. Here we have examined the influence of maternal dietary zinc supplementation during pregnancy and lactation on the development of ASD-associated behavioural and synaptic changes in the offspring Shank3 knockout (Shank3−/−) mice. Behavioural and electrophysiological experiments were performed in juvenile and adult Shank3−/− and wildtype littermate control mice born from mothers fed control (30 ppm, ppm) or supplemented (150 ppm) dietary zinc. We observed that the supplemented maternal zinc diet prevented ASD-associated deficits in social interaction and normalised anxiety behaviours in Shank3−/− offspring mice. These effects were maintained into adulthood. Repetitive grooming was also prevented in adult Shank3−/− offspring mice. At the synaptic level, maternal zinc supplementation altered postsynaptic NMDA receptor-mediated currents and presynaptic function at glutamatergic synapses onto medium spiny neurons in the cortico-striatal pathway of the Shank3−/− offspring mice. These data show that increased maternal dietary zinc during pregnancy and lactation can alter the development of ASD-associated changes at the synaptic and the behavioural levels, and that zinc supplementation from the beginning of brain development can prevent ASD-associated deficits in Shank3−/− mice long term.
Highlights
Autism Spectrum Disorders (ASDs) are clinically diagnosed by the presence of behavioural symptoms in two core criteria: A) impairments in social communication, and B) restricted and repetitive behaviours [3]
No significant difference in growth was observed between breeders that were fed with the two different zinc diets (Supplementary Figure 1A)
With regards to the growth of Shank3-wildtype and Shank3−/− offspring from the maternal supplemented and control zinc diets, we found no significant differences in weight were observed at either 3, 9, or 16 weeks of age (3 weeks: pvalue = 0.21, Supplementary Figure 1C; 9 weeks: pvalue = 0.79, Supplementary Figure 1D; 16 weeks: pvalue = 0.55, Supplementary Figure 1E)
Summary
Autism Spectrum Disorders (ASDs) are clinically diagnosed by the presence of behavioural symptoms in two core criteria: A) impairments in social communication, and B) restricted and repetitive behaviours [3]. Several lines of Shank mutant mice have been created with germline deletions of Shank exons encoding different Shank protein domains, these Shank3−/− models consistently present deficits in social interactions and heightened self-grooming [10, 21, 33, 36, 50, 57, 65, 66, 70, 72, 73]. The phenotypic variability evident between different Shank3−/− mouse models could be attributable to the differences in Shank exon(s) deleted, animal age at experiment, and sex examined. This variability is consistent with the clinical heterogeneity observed in patients with ASD-associated SHANK3 mutations
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