Alpha7 nicotinic acetylcholine receptor agonist promotes retinal ganglion cell function via modulating GABAergic presynaptic activity in a chronic glaucomatous model.
Alpha7 nicotinic acetylcholine receptor agonist promotes retinal ganglion cell function via modulating GABAergic presynaptic activity in a chronic glaucomatous model.
复制标题
Alpha7 烟碱乙酰胆碱受体激动剂通过调节慢性青光眼模型中 GABA 突触前活动促进视网膜神经节细胞功能
DOI：
10.1038/s41598-017-02092-6
复制
发表时间：
2017-05-11
影响因子：
4.6
通讯作者：
Wu J
中科院分区：
文献类型：
--
作者：
Zhou X;Cheng Y;Zhang R;Li G;Yang B;Zhang S;Wu J
α-7烟碱乙酰胆碱受体（α7-nAChR）激动剂可以防止谷氨酸诱导的视网膜神经节细胞（RGCs）兴奋性毒性。然而，PNU-282987（一种α7-nAChR激动剂）在慢性体内大鼠青光眼模型中的神经保护作用和作用机制尚不清楚。我们发现，眼内压（IOP）升高下调视网膜α7-nAChR表达。视网膜电图显示，明视负性反应（PhNR）的幅度下降与由IOP升高引起的RGC的损失平行。PNU-282987增强RGC活力和功能，并降低RGC中末端脱氧核苷酸转移酶dUTP缺口末端标记（TUNEL）阳性信号。膜片钳记录显示，对照组和昏迷组视网膜切片之间RGCs的微型GABA能抑制性突触后电流（mIPSC）的基线频率和衰减时间存在差异。蛋白质印迹和免疫染色结果表明，谷氨酸脱羧酶65/67和GABA缺陷持续存在于昏迷视网膜中，这些缺陷被PNU-282987逆转。膜片钳记录还显示PNU-282987显著增加RGC的GABA能mIPSC的频率和振幅。玻璃体内给予选择性GABAA受体拮抗剂可阻断PNU-292987的保护作用。PNU-282987对GABA能突触传递的调节导致神经节细胞回路去兴奋并抑制兴奋性毒性过程。
Alpha-7 nicotinic acetylcholine receptor (α7-nAChR) agonists can prevent glutamate-induced excitotoxicity in cultured retinal ganglion cells (RGCs). However, the neuroprotective effects and the mechanism of action of PNU-282987, an α7-nAChR agonist, in a chronic in vivo rat glaucoma model are poorly understood. We found that elevated intraocular pressure (IOP) downregulated retinal α7-nAChR expression. Electroretinography revealed that the amplitude of the photopic negative response (PhNR) decreased in parallel with the loss of RGCs caused by elevated IOP. PNU-282987 enhanced RGC viability and function and decreased terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive signals in RGCs. Patch-clamp recordings revealed differences in the baseline frequencies and decay times of the miniature GABAergic inhibitory postsynaptic currents (mIPSCs) of RGCs between control and glaucomatous retinal slices. The results of western blotting and immunostaining showed that glutamic acid decarboxylase 65/67 and GABA deficits persisted in glaucomatous retinas and that these deficits were reversed by PNU-282987. Patch-clamp recordings also showed that PNU-282987 significantly increased the frequency and amplitude of the GABAergic mIPSCs of RGCs. The protective effects of PNU-292987 were blocked by intravitreal administration of selective GABAA receptor antagonists. The modulation of GABAergic synaptic transmission by PNU-282987 causes de-excitation of ganglion cell circuits and suppresses excitotoxic processes.