NMDA受体与GABAa受体相互作用在水杨酸钠诱导的螺旋神经节神经元损害中的研究

NMDA受体与GABAa受体相互作用涉及多种神经生理过程，但其在神经元兴奋毒性等病理过程中的作用尚属未知。我们前期研究发现，NMDA受体和GABAa受体均参与了水杨酸钠诱导的螺旋神经节神经元（SGNs）的损害，NMDA受体介导下调GABAa受体的表达。据此我们推测：NMDA受体与GABAa受体相互作用介导了水杨酸钠造成的SGNs损伤。为验证这一假说，我们拟采用膜片钳记录、细胞钙成像、免疫荧光和激光共聚焦显微镜、实时荧光PCR、基因重组等技术，观察水杨酸钠作用后，SGNs中NMDA受体和GABAa受体相互作用对受体功能的影响，及受体在分子、蛋白和细胞水平表达的变化；研究细胞内钙离子、受体转运和受体磷酸化对这两受体间相互作用的影响，并确定两受体相互作用的亚单位。从而从多角度、多层面阐述这两受体间相互作用介导水杨酸钠诱导的SGNs损伤的机制，为研究耳毒性的深层机制提供新的思路。

The cross-talk between receptors plays a critical role in both physiological and pathological processes. It is well known that the interaction between NMDA and GABAa receptors involves in the regulation of neural transmission and synaptic plasticity. However, the mechanism of this interaction in neuronal excitotoxicity remains unclear. Our previous study showed that sodium salicylate-induced excitotoxicity was mediated by both NMDA and GABAa receptors in spiral ganglion neurons (SGN) and NMDA receptor caused down-regulation of GABAa receptors expression in SGN. We hypothesize that the ototoxicity induced by salicylate is associated with interaction between NMDA and GABAa receptors in SGN. In this study, we will detect protein and mRNA expression changes of NMDA and GABAa receptors in SGN after sodium salicylate application by immunofluorescence staining, western blot and real-time PCR. Moreover, the electrophysiological assessment of SGN NMDA and GABAa receptors interaction induced by salicylate will be performed by patch clamp recording. We will also investigate the function role of intracellular Ca2+，receptor trafficking and phosphorylation in this process. Finally, we will identify the critical subunit segment for interaction of NMDA and GABAa receptors. In summary, the mechanism of SGN's NMDA and GABAa receptors interaction in salicylate-induced ototoxicity will be investigated in multiple disciplines,which will lead to more insights into the excitotoxicity mechanism, paving the way for novel biomedical interventions to prevention and treatment of drug-induced hearing impairment.