PTEN介导NR2B磷酸化/CREB通路调控的突触可塑性参与大鼠偏头痛慢性化的维持机制

Central sensitization in the trigeminal nucleus caudalis(TNC) is a key of transformation of chronic migraine(CM), but precise mechanism is not known yet. Phosphorylation of the NR2B subunit of the NMDA receptor triggering formation and maintenance of Long-term potentiation (LTP) of synaptic plasticity is the pathological foundation of central sensitization in chronic pain. We had reported that downregulation PTEN in the trigeminal ganglia of rats with nitroglycerin-induced migraine may alleviate migraine attack, its mechanisms is likely to associated with PTEN reducing neuronal excitability at NR2B and CREB(cAMP response element-binding protein)-modulated LTP level. Meanwhile, our preliminary result found that there was increase of PTEN and NR2B-pTyr1472 and CREB expression in neurons within TNC of chronic migraine rats induced by Inflammatory Soup(IS). Then, we speculate that elevation of PTEN causing high level of NR2B phosphorylation and CREB may trigger LTP resulting in chronic migraine. To illuminate PTEN-mediated “PTEN/NR2B-phospho/CREB” signal pathway participate the maintenance of the chronification of migraine in rats, this study will plan to establish SD rats model of CM with IS and NOC-18, and transfected PTEN gene adenovirus, then the expression of PTEN , NR2B-phospho, CREB as well as electrophysiology and the behavioral change were measured by QT-PCR, Western blotting, von Frey monofilament and patch clamp et al. These results will be able to answer a scientific problem, that is, the transformed mechanisms of chronic migraine may be due to central sensitization induced by PTEN causing the increase of NR2B-phospho and CREB triggering LTP, which will find novel targets for prevention and therapy of chronic migraine.

三叉神经尾核（TNC）“中枢致敏”是慢性偏头痛(CM)转化的关键，确切机制不明。NR2B磷酸化触发突触可塑性LTP的形成和维持是慢性疼痛中枢致敏的病理基础。我们已报道下调三叉神经节PTEN缓解偏头痛的机制可能与PTEN降低NR2B的神经兴奋性及CREB调控的LTP有关，预实验发现CM大鼠TNC区神经元有PTEN和NR2B-pTyr表达升高，我们推测CM可能因PTEN升高导致NR2B磷酸化和CREB增加触发LTP所致。为阐明PTEN所介导的NR2B磷酸化/CREB通路在维持偏头痛慢性化中的作用，本课题拟在CM大鼠模型上，转染PTEN腺病毒，用分子生物学、行为学及膜片钳等技术，测相关脑区PTEN、NR2B磷酸化、CREB等的表达、鼠行为学及电生理等改变，本研究将回答CM转化机制可能是由PTEN激活NR2B磷酸化和CREB升高触发LTP引起的“中枢致敏”所致这一科学问题，也可为CM防治提供新靶点

慢性偏头痛（Chronic Migraine，CM）是一种致残的神经系统疾病，已被WHO列为四大最严重的慢性功能障碍性疾病之一。为了证明CM可能因PTEN升高导致NR2B磷酸化和CREB增加触发LTP所致这一科学假说；根据本课题组已有的报道，证实了PTEN对NR2B-Tyr存在调控关系之后，本项目重点针对NR2B酪氨酸磷酸化调节的突触可塑性引起的“中枢敏化”与CM发病机制的关系展开研究。. 目前本项目仍延用硬脑膜“炎性汤”滴注方式建立CM大鼠模型，证明了（1）NR2B-pTyr可以通过调节突触可塑性参与CM中枢敏化，抑制NR2B-pTyr具有保护作用；（2）星形胶质细胞上EAAT2的激活可以通过增加谷氨酸清除，减少NR2B磷酸化，继而调节突触可塑性相关的中枢敏化，在CM中发挥保护作用；（3）神经元上ephrinB/EphB2及mGluR5的上调可以通过介导NR2B-pTyr/CaMKⅡ/pCREB 信号通路参与突触可塑性的调控，促进中枢敏化，诱导偏头痛慢性化发展，而抑制ephrinB/EphB2及mGluR5则可以缓解偏头痛慢性化；（4）抑制性中间神经元数量及功能的下降，通过GABABR2/PKA/SynCAM1信号途径促进了谷氨酸的过度堆积，参与了CM大鼠谷氨酸介导的中枢敏化，并且GABABR2与突触可塑性的调节紧密相关；（5）SIRT1介导的线粒体功能障碍和mGluR5依赖的自噬调节均参与CM中枢敏化机制；（6）神经生长因子（NGF）在CM中对酸敏感离子通道3（ASIC3) 有调控作用，它们也参与了CM的发病机制。. 这些结果阐明了慢性偏头痛中有突触可塑性的改变，突触可塑性引起的“中枢敏化”是偏头痛慢性化的维持机制。证明了NR2B磷酸化及其相关通路调控的神经元突触可塑性引起的“中枢敏化”，是CM的发病机制之一。本项目为丰富和拓展CM发病机制，提供了实验依据；对提高CM防治的有效性和减少副作用，都是有益的探索和具有重大的意义。同时，本研项目也为本课题组将来从线粒体能量代谢失衡和GABA能中间神经元功能受损导致神经元兴奋抑制平衡功能失调等新角度，探索CM的发病及防治机制找到了新的切入点。. 本项目已发表SCI论著7篇，在CSCD期刊上发表论文2篇；培养硕士生8名；培养青年科技人员2名；较好地按计划书完成了本项目。

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