Regulation of CRMP2 by Cdk5 and GSK-3β participates in sevoflurane-induced dendritic development abnormalities and cognitive dysfunction in developing rats
Regulation of CRMP2 by Cdk5 and GSK-3β participates in sevoflurane-induced dendritic development abnormalities and cognitive dysfunction in developing rats
复制标题
CDK5和GSK-3β调控CRMP2参与七氟醚致发育大鼠树突状细胞发育异常和认知功能障碍
DOI：
10.1016/j.toxlet.2021.01.023
复制
发表时间：
2021-02-11
影响因子：
3.5
通讯作者：
Li, Yujuan
中科院分区：
文献类型：
--
作者：
Liao, Zhaoxia;Huang, Zeqi;Li, Yujuan
背景：七氟醚等全身麻醉药干扰树突状细胞的发育和突触发生，导致认知功能障碍。崩解素反应介质蛋白2(CRMP2)在树突状细胞发育和突触可塑性中起重要作用，其磷酸化受细胞周期蛋白依赖性激酶-5(CDK5)和糖原合成酶-3β(GSK-3β)的调节。我们研究了CDK5/CRMP2或GSK-3β/CRMP2通路是否参与了七氟醚所致的发育性神经毒性。注射CDK5抑制剂罗斯科维汀、GSK-3β抑制剂SB415286或生理盐水20min。在2.8%七氟醚暴露4h前，用Western-blotting检测七氟醚暴露6h后海马区CDK5/CRMP2和GSK-3β/CRMP2通路蛋白的表达。当大鼠成长到青春期(从PND25开始)时，进行旷场和情景恐惧条件反射测试，记录海马片的长时程增强(LTP)，高尔基染色观察锥体神经元的形态，Western-blotting检测突触可塑性相关蛋白在海马区的表达。结果：七氟醚可激活新生大鼠海马区CDK5/CRMP2和GSK-3β/CRMP2通路，减少锥体细胞树突长度、分支和密度。降低海马区PSD-95、DREBRIN和突触素的表达，降低大鼠的记忆能力，抑制海马片LTP的表达。预先给予CDK5或GSK-3β抑制剂可减弱七氟醚的上述损伤作用。结论：CDK5/CRMP2和GSK-3β/CRMP2通路参与了七氟醚诱导的发育中大鼠树突状细胞发育异常和认知功能障碍。(C)爱思唯尔出版的《2021年》。
Background: General anesthetics such as sevoflurane interfere with dendritic development and synaptogenesis, resulting in cognitive impairment. The collapsin response mediator protein2 (CRMP2) plays important roles in dendritic development and synaptic plasticity and its phosphorylation is regulated by cycline dependent kinase-5 (Cdk5) and glycogen synthase kinase-3 beta (GSK-3 beta). Here we investigated whether Cdk5/CRMP2 or GSK-3 beta/CRMP2 pathway is involved in sevoflurane-induced developmental neurotoxicity.Methods: Rats at postnatal day 7 (PND7) were i.p. injected with Cdk5 inhibitor roscovitine, GSK-3 beta inhibitor SB415286 or saline 20 min. before exposure to 2.8% sevoflurane for 4 h. Western-blotting was applied to measure the expression of Cdk5/CRMP2 and GSK-3 beta/CRMP2 pathway proteins in the hippocampus 6 h after the sevoflurane exposure. When rats grew to adolescence (from PND25), they were tested for open-field and contextual fear conditioning, and then long term potentiation (LTP) from hippocampal slices was recorded, and morphology of pyramidal neuron was examined by Golgi staining and synaptic plasticity-related proteins expression in hippocampus were measured by western-blotting. In another batch of experiment, siRNA-CRMP2 or vehicle control was injected into hippocampus on PND5.Results: Sevoflurane activated Cdk5/CRMP2 and GSK-3 beta/CRMP2 pathways in the hippocampus of neonatal rats, reduced dendritic length, branches and the density of dendritic spine in pyramidal neurons. It also reduced the expressions of PSD-95, drebrin and synaptophysin in hippocampus, impaired memory ability of rats and inhibited LTP in hippocampal slices. All the impairment effects by sevoflurane were attenuated by pretreatment with inhibitor of Cdk5 or GSK-3 beta. Furthermore, rat transfected with siRNA-CRMP2 eliminated the neuroprotective effects of Cdk5 or GSK-3 beta blocker in neurobehavioral and LTP tests.Conclusion: Cdk5/CRMP2 and GSK-3 beta/CRMP2 pathways participate in sevoflurane-induced dendritic development abnormalities and cognitive dysfunction in developing rats. (C) 2021 Published by Elsevier B.V.