Xylene and its derivatives are known to be neurotoxic to the central nervous system of animals. Our previous work has shown that para-xylene (PX) can cause an increase in apoptotic cells and abnormal avoidance behavior in Xenopus laevis. However, the mechanism underlying the impact of PX on neuronal structural and functional plasticity is less clear. Here, we examined the effects of PX on neuronal development and plasticity in the developing optic tectum. We found that HuC/D-positive neurons were more vulnerable than SOX2-positive progenitor cells or BLBP-positive radial glial cells after exposure to PX at 1 mM for 48 h. The further measurement of postsynaptic receptors and synaptic vesicle proteins showed that the expression levels of GluA1 and GluA2, but not Rab3a and SNAP25, were significantly decreased in the tectal brain. In vivo time-lapse images and electrophysiological recordings showed that PX exposure resulted in significant deficits in neuronal structure, particularly in the total dendritic branch length (TDBL), and visual stimulation-induced excitatory compound synaptic currents (eCSCs) without altering neurotransmitter release probability. Strikingly, coexposure to d-glucuronolactone (GA) and PX rescued the structural and functional deficits caused by PX exposure alone. Furthermore, we found that visual experience-induced structural, functional and behavioral plasticity was blocked by PX exposure, which was also rescued by the simultaneous administration of GA and PX . Thus, our findings indicate that PX is neurotoxic to brain development and plasticity and that GA may be considered a promising candidate to treat PX-induced defects in neural circuits.

译文

二甲苯及其衍生物已知对动物的中枢神经系统具有神经毒性。我们先前的工作表明,对二甲苯 (PX) 可以引起非洲爪蟾凋亡细胞的增加和异常的回避行为。然而,PX对神经元结构和功能可塑性影响的潜在机制尚不清楚。在这里,我们研究了PX对发育中的视神经的发育和可塑性的影响。我们发现,在暴露于1毫米的PX 48小时后,HuC/D阳性神经元比SOX2-positive祖细胞或BLBP阳性的放射状神经胶质细胞更脆弱。对突触后受体和突触小泡蛋白的进一步测量表明,在大脑皮层中GluA1和GluA2的表达水平显着降低,而Rab3a和SNAP25的表达水平却没有降低。体内延时图像和电生理记录显示,PX暴露导致神经元结构显着缺陷,尤其是总树突分支长度 (TDBL) 和视觉刺激诱导的兴奋性复合突触电流 (eCSCs),而不改变神经递质释放概率。令人惊讶的是,共同暴露于d-葡萄糖醛酸内酯 (GA) 和PX可挽救仅由PX暴露引起的结构和功能缺陷。此外,我们发现视觉体验诱导的结构,功能和行为可塑性被PX暴露所阻断,而同时施用GA和PX也可以挽救。因此,我们的发现表明PX对大脑发育和可塑性具有神经毒性,并且GA可能被认为是治疗PX诱导的神经回路缺陷的有希望的候选者。

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