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.

中文翻译：

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母体补锌对后代Shank3基因敲除小鼠自闭症相关行为和突触缺陷发展的影响。

自闭症谱系障碍（ASD）的特征是社交互动不足和重复行为。已在Shank蛋白质家族中鉴定出多种与ASD相关的突变，这些突变在谷氨酸能突触的结构和可塑性中起关键作用，导致突触功能受损和小鼠中与ASD相关的行为缺陷的表现。小腿蛋白受锌的高度调节，锌与小腿SAM结构域结合以驱动突触蛋白募集和突触成熟。在这里，我们检查了孕期和哺乳期孕妇补锌对后代Shank3基因敲除（Shank3-/-）小鼠中ASD相关行为和突触变化发展的影响。行为和电生理实验是在幼年和成年的Shank3-/-和野生型同窝对照小鼠中进行的，这些小鼠是从饲喂对照（30 ppm，ppm）或补充（150 ppm）饮食锌的母亲那里出生的。我们观察到补充的母体锌饮食可以预防Shank3-/-后代小鼠的社交互动中ASD相关的缺陷和正常化的焦虑行为。这些作用一直维持到成年。成年的Shank3-/-后代小鼠中也避免了重复修饰。在突触水平，母体补锌改变了Shank3-/-后代小鼠皮质-纹状体途径中谷氨酸能突触到中突棘神经元的突触后NMDA受体介导的电流和突触前功能。