发育早期nano-SiO2暴露致自闭症样行为发生的分子机制研究

Abnormal neural circuit caused by the developmental imbalance of excitatory/inhibitory synapses during the critical period of cortex development plays an important role in autism. Nano-SiO2 exposure may cause obvious toxicity of nervous system during this period. We have found that Nano-SiO2 exposure could contribute to autism-like behaviors. It has been confirmed that IL-6 could affect the imbalance of excitatory/inhibitory synapses, and abnormal microglia and IL-6 expression in cortex were also observed in our previous experiments. These suggest that excessive IL-6 produced by activated microglia may result in synaptic developmental disorders and autism-like behaviors during critical period of cortex development. However, the exact mechanism is still unclear. In our study, Thy1-EGFP mice are used to examine the developmental imbalance of excitatory/inhibitory synapses based on the evaluation of ethology and synaptic proteins after Nano-SiO2 exposure during critical period of cortex development. Neural circuit is detected by patch clamp and fMRI. In vitro, the effect of microglia on neuron is evaluated by co-culture and SiRNA. Illuminating the exact mechanism of autism-like behaviors caused by Nano-SiO2 exposure may provide a new way for prevention and control of autism.

皮层发育关键期兴奋/抑制突触发育失衡引起的环路异常是自闭症发生的重要病理生理机制。发育早期暴露纳米二氧化硅颗粒可能产生明显的神经系统毒性作用，我们前期研究发现新生小鼠皮层发育关键期暴露纳米二氧化硅颗粒将致成年产生自闭症样行为。已经证实IL-6影响兴奋/抑制突触的平衡，我们观察到皮层内小胶质细胞过度激活及IL-6释放增加；因此推测在皮层发育关键期纳米二氧化硅颗粒暴露可能通过激活小胶质细胞分泌过量IL-6引起突触发育障碍，从而引起自闭症样行为，但目前机制仍不清楚。本课题拟采用Thy1-EGFP小鼠，结合行为学与突触蛋白检测分析发育早期暴露纳米二氧化硅颗粒后对皮层发育关键期突触发育的影响；采用膜片钳、fMRI等技术分析神经环路的变化；离体条件下采用RNA干扰结合共培养技术检测小胶质细胞对神经元功能活动的调控；从而阐明发育早期暴露纳米二氧化硅颗粒引起自闭症样行为的机制，为自闭症的防治提供新线索。

纳米二氧化硅颗粒（SiO2-NPs）是最常用的纳米材料之一，它具有较强的化学稳定性、强修饰性和增加的表面体积比等特殊的物理化学特性。因此，纳米二氧化硅颗粒被广泛应用于化工、电子、化妆品和医药制造等领域。近年来，研究显示纳米二氧化硅颗粒能够对机体的脑、肝、肾等一系列器官产生影响，但是关于该颗粒对神经系统发育的影响却很少报道。我们本研究通过对新生小鼠暴露荧光标记的纳米二氧化硅颗粒，检测颗粒对小鼠成年后的行为改变，通过分子生物学和形态学的实验方法探索纳米二氧化硅颗粒暴露对小鼠神经发育的影响机制。研究结果显示，新生小鼠纳米二氧化硅颗粒连续暴露一周后，小鼠肺部发现荧光标记的纳米二氧化硅颗粒。行为学检测发现纳米二氧化硅颗粒能够导致小鼠成年后出现自闭样行为和轻度焦虑行为。进一步探究发现小鼠海马齿状回小胶质细胞数量明显增加和炎症因子表达升高，以及海马神经前体细胞增殖受到抑制，且存在剂量相关性。这些结果提示新生期纳米二氧化硅颗粒暴露能够导致机体成年后的自闭样行为可能与颗粒导致海马炎症和神经前提细胞异常增殖有关。本研究为今后纳米颗粒毒性和自闭症的研究提供了一定的参考。