Biotechnology Research and Training Center, University of North Carolina-Pembroke, Pembroke, North Carolina, USA.
Department of Biology, University of North Carolina-Pembroke, Pembroke, North Carolina, USA.
Sci Rep. 2019 Apr 25;9(1):6532. doi: 10.1038/s41598-019-42934-z.
Organophosphates account for many of the world's deadliest poisons. They inhibit acetylcholinesterase causing cholinergic crises that lead to seizures and death, while survivors commonly experience long-term neurological problems. Here, we treated brain explants with the organophosphate compound paraoxon and uncovered a unique mechanism of neurotoxicity. Paraoxon-exposed hippocampal slice cultures exhibited progressive declines in synaptophysin, synapsin II, and PSD-95, whereas reduction in GluR1 was slower and NeuN and Nissl staining showed no indications of neuronal damage. The distinctive synaptotoxicity was observed in dendritic zones of CA1 and dentate gyrus. Interestingly, declines in synapsin II dendritic labeling correlated with increased staining for β1 integrin, a component of adhesion receptors that regulate synapse maintenance and plasticity. The paraoxon-induced β1 integrin response was targeted to synapses, and the two-fold increase in β1 integrin was selective as other synaptic adhesion molecules were unchanged. Additionally, β1 integrin-cofilin signaling was triggered by the exposure and correlations were found between the extent of synaptic decline and the level of β1 integrin responses. These findings identified organophosphate-mediated early and lasting synaptotoxicity which can explain delayed neurological dysfunction later in life. They also suggest that the interplay between synaptotoxic events and compensatory adhesion responses influences neuronal fate in exposed individuals.
有机磷化合物是世界上许多致命毒物的罪魁祸首。它们抑制乙酰胆碱酯酶，导致胆碱能危机，从而引发癫痫和死亡，而幸存者通常会经历长期的神经问题。在这里，我们用有机磷化合物对脑外植体进行了处理，发现了一种独特的神经毒性机制。经对氧磷处理的海马切片培养物中突触小体素、突触素 II 和 PSD-95 逐渐减少，而 GluR1 的减少较慢，NeuN 和尼氏染色显示神经元没有损伤的迹象。这种独特的突触毒性在 CA1 和齿状回的树突区观察到。有趣的是，突触素 II 树突标记的减少与β1 整合素的染色增加有关，β1 整合素是调节突触维持和可塑性的黏附受体的一个组成部分。对氧磷诱导的β1 整合素反应针对突触，并且β1 整合素的两倍增加是选择性的，因为其他突触黏附分子没有改变。此外，β1 整合素-丝切蛋白信号被暴露触发，并且发现突触减少的程度与β1 整合素反应的水平之间存在相关性。这些发现确定了有机磷介导的早期和持久的突触毒性，这可以解释生命后期延迟的神经功能障碍。它们还表明，突触毒性事件和代偿性黏附反应之间的相互作用影响暴露个体的神经元命运。
