Department of Biomedical, Metabolic and Neural Sciences, Center for Neuroscience and Neurotechnology, University of Modena and Reggio Emilia, Modena, Italy.
Cellular Neurobiology and Neuro-Nanotechnology lab, Department of Biological Sciences, University of Limerick, Limerick, Ireland.
Transl Psychiatry. 2021 Nov 5;11(1):562. doi: 10.1038/s41398-021-01694-z.
Autism Spectrum Disorders (ASD) are caused by a combination of genetic predisposition and nongenetic factors. Among the nongenetic factors, maternal immune system activation and zinc deficiency have been proposed. Intriguingly, as a genetic factor, copy-number variations in S100B, a pro-inflammatory damage-associated molecular pattern (DAMP), have been associated with ASD, and increased serum S100B has been found in ASD. Interestingly, it has been shown that increased S100B levels affect zinc homeostasis in vitro. Thus, here, we investigated the influence of increased S100B levels in vitro and in vivo during pregnancy in mice regarding zinc availability, the zinc-sensitive SHANK protein networks associated with ASD, and behavioral outcomes. We observed that S100B affects the synaptic SHANK2 and SHANK3 levels in a zinc-dependent manner, especially early in neuronal development. Animals exposed to high S100B levels in utero similarly show reduced levels of free zinc and SHANK2 in the brain. On the behavioral level, these mice display hyperactivity, increased stereotypic and abnormal social behaviors, and cognitive impairment. Pro-inflammatory factors and zinc-signaling alterations converge on the synaptic level revealing a common pathomechanism that may mechanistically explain a large share of ASD cases.
自闭症谱系障碍（ASD）是由遗传易感性和非遗传因素共同引起的。在非遗传因素中，母体免疫系统激活和锌缺乏已被提出。有趣的是，作为遗传因素，S100B 的拷贝数变异，一种促炎损伤相关分子模式（DAMP），与 ASD 相关，并且在 ASD 中发现血清 S100B 增加。有趣的是，已经表明增加的 S100B 水平会影响体外的锌稳态。因此，在这里，我们研究了在怀孕期间体外和体内增加 S100B 水平对锌可用性、与 ASD 相关的锌敏感 SHANK 蛋白网络以及行为结果的影响。我们观察到 S100B 以锌依赖的方式影响突触 SHANK2 和 SHANK3 水平，尤其是在神经元发育早期。在子宫内暴露于高 S100B 水平的动物的大脑中同样显示出游离锌和 SHANK2 水平降低。在行为水平上，这些小鼠表现出多动、刻板和异常的社交行为以及认知障碍。促炎因子和锌信号转导的改变在突触水平上汇聚，揭示了一种共同的发病机制，可能从机制上解释了大量 ASD 病例。
