Neural reprogramming in retinal degeneration
Neural reprogramming in retinal degeneration
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DOI：
10.1167/iovs.07-0032
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发表时间：
2007-07-01
影响因子：
4.4
通讯作者：
Lucas, Robert J.
中科院分区：
文献类型：
--
作者：
Marc, Robert E.;Jones, Bryan W.;Lucas, Robert J.
目的.视网膜色素变性（retinitis pigmentosa，RP）等退行性疾病的早期视觉缺陷可能是由神经视网膜的阶段性重塑引起的。作者试图探索离子型（iGluR）和第3组6型代谢型（mG1uR6）谷氨酸受体在晚期光感受器变性中的功能表达。使用有机阳离子的激发映射和计算分子表型来确定视网膜神经元是否在视网膜变性的啮齿动物模型和人RP样品中显示功能性谷氨酸受体信号传导。在RP的啮齿动物模型中，光感受器丧失后，双极细胞失去mGluR6和iGluR谷氨酸激活电流，而无长突细胞和神经节细胞保留iG1uR介导的反应性。偶然的是，无长突细胞和神经节细胞在体内显示自发的iGluR信号，即使双极细胞缺乏谷氨酸偶联的去极化机制。视锥细胞存活可以通过OFF双极细胞拯救iGluR表达。在一个有视锥保留的人RP病例中，iGluR信号似乎是完整的，但表达功能性iG1uRs的双极细胞数量是正常视网膜的两倍。RP触发双极细胞谷氨酸受体表达的永久性丧失，虽然自发的iG1uR介导的无长突细胞和神经节细胞的信号传导意味着这种截短的双极细胞仍然释放谷氨酸响应于一些非谷氨酸能去极化。保留焦锥可以通过附近的双极细胞保留iGluR展示，这可能有助于后期RP感光细胞移植尝试。人类RP的一个实例提供了证据，杆双极细胞树突转换可能会触发新的基因表达模式，并可能损害视锥细胞通路功能。
PURPOSE. Early visual defects in degenerative diseases such as retinitis pigmentosa (RP) may arise from phased remodeling of the neural retina. The authors sought to explore the functional expression of ionotropic (iGluR) and group 3, type 6 metabotropic (mG1uR6) glutamate receptors in late-stage photoreceptor degeneration.Methods. Excitation mapping with organic cations and computational molecular phenotyping were used to determine whether retinal neurons displayed functional glutamate receptor signaling in rodent models of retinal degeneration and a sample of human RP.Results. After photoreceptor loss in rodent models of RP, bipolar cells lose mGluR6 and iGluR glutamate-activated currents, whereas amacrine and ganglion cells retain iG1uR-mediated responsivity. Paradoxically, amacrine and ganglion cells show spontaneous iGluR signals in vivo even though bipolar cells lack glutamate-coupled depolarization mechanisms. Cone survival can rescue iGluR expression by OFF bipolar cells. In a case of human RP with cone sparing, iGluR signaling appeared intact, but the number of bipolar cells expressing functional iG1uRs was double that of normal retina.Conclusions. RP triggers permanent loss of bipolar cell glutamate receptor expression, though spontaneous iG1uR-mediated signaling by amacrine and ganglion cells implies that such truncated bipolar cells still release glutamate in response to some nonglutamatergic depolarization. Focal cone- sparing can preserve iGluR display by nearby bipolar cells, which may facilitate late RP photoreceptor transplantation attempts. An instance of human RP provides evidence that rod bipolar cell dendrite switching likely triggers new gene expression patterns and may impair cone pathway function.