Zhejiang Provincial Clinical Research Center for Mental Illness, The Affiliated Kangning Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; School of Mental Health, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
School of Mental Health, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
Brain Res. 2022 Apr 1;1780:147802. doi: 10.1016/j.brainres.2022.147802. Epub 2022 Jan 24.
Cuprizone (CPZ) is a copper-chelator and toxic to mitochondria. Recent studies have shown oligodendrocyte (OL) loss and demyelination along with dopamine (DA) increase and behavioral abnormalities in CPZ-exposed mice, demonstrating its application in schizophrenia research. This study examined effects of CPZ exposure on autonomous behavior and dopaminergic neurotransmission in larval zebra fish. CPZ exposure was found to reduce the swimming velocity of zebra fish thus decreased swimming distance during day and night time. Moreover, the treatment induced a movement response of zebra fish larvae reacting to light-on/off switch featured by swimming velocity increase and decrease during the first and second half of the light-on/off phase, respectively. But, it abolished responses of zebra fish to sound-on/off seen in Control group. HPLC analysis showed elevated DA levels in the zebra fish, no change in NE and 5-HT levels. Transcriptome analysis reported changes in gene expression related to dopaminergic synapse and oxidative phosphorylation in CPZ-exposed larvae relative to Control group. Of the gene expression changes, up-regulation of drd2a, drd2b, drd4a and drd4rs was confirmed by RT-PCR, although no difference existed between Control and CPZ groups in dopaminergic neuron numbers. These results demonstrated dopaminergic hyperactivity and locomotor deficit in CPZ-exposed zebra fish larvae, encouraging further application of this model in exploring neurotoxic effects of CPZ on mitochondria and dopaminergic neurotransmission in zebra fish.
铜螯合剂 CPZ 对线粒体有毒。最近的研究表明，CPZ 暴露的小鼠会出现少突胶质细胞（OL）丢失和脱髓鞘，以及多巴胺（DA）增加和行为异常，这表明它可用于精神分裂症研究。本研究检查了 CPZ 暴露对斑马鱼幼虫自主行为和多巴胺能神经传递的影响。结果发现 CPZ 暴露降低了斑马鱼的游动速度，从而减少了昼夜游动的距离。此外，该处理诱导了斑马鱼幼虫对光开关的运动反应，其特征是在光开/关相的前半部分和后半部分分别增加和减少游动速度。但是，它消除了对照组中斑马鱼对声音开/关的反应。HPLC 分析显示，斑马鱼中的 DA 水平升高，NE 和 5-HT 水平不变。转录组分析报告了 CPZ 暴露幼虫中与多巴胺能突触和氧化磷酸化相关的基因表达变化，与对照组相比。在 CPZ 暴露的幼虫中，drd2a、drd2b、drd4a 和 drd4rs 的表达上调得到了 RT-PCR 的证实，尽管对照组和 CPZ 组之间多巴胺能神经元数量没有差异。这些结果表明 CPZ 暴露的斑马鱼幼虫存在多巴胺能活性亢进和运动缺陷，鼓励进一步应用该模型来探索 CPZ 对线粒体和多巴胺能神经传递的神经毒性作用。
