Differential effects of AAV.BDNF and AAV.Ntf3 in the deafened adult guinea pig ear.
Differential effects of AAV.BDNF and AAV.Ntf3 in the deafened adult guinea pig ear.
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DOI：
10.1038/srep08619
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发表时间：
2015-03-02
影响因子：
4.6
通讯作者：
Raphael Y
中科院分区：
文献类型：
--
作者：
Budenz CL;Wong HT;Swiderski DL;Shibata SB;Pfingst BE;Raphael Y
耳蜗毛细胞损失导致外周听觉纤维（PAF）二次退化和螺旋神经节神经元（SGN）损失。人工耳蜗 (CI) 在恢复听力方面的性能取决于 SGN 的存活率。在这里，我们比较了带有神经营养蛋白基因插入的腺相关病毒载体 AAV.BDNF 和 AAV.Ntf3 对全身（卡那霉素和呋塞米）或局部（新霉素）耳聋的豚鼠耳朵的影响。豚鼠耳聋一周后将 AAV.BDNF 或 AAV.Ntf3 递送至耳蜗，并在 3 个月后对耳朵进行形态学评估。当时，耳蜗液中的神经营养蛋白水平并未显着升高，尽管体外和短期体内实验表明这些病毒载体的神经营养蛋白水平显着升高。然而，接受这些载体的动物在基底膜区域表现出相当大的 PAF 重新生长。在系统性耳聋动物中，分化的支持细胞和 PAF 的存在之间存在负相关，这表明支持细胞影响旨在增强耳蜗神经基质的神经营养蛋白过度表达的结果。 Rosenthal 管中 SGN 的计数表明 BDNF 在保存 SGN 方面比 NT-3 更有效。结果表明，神经营养素水平的短暂升高可以长期维持耳蜗神经基质。
Cochlear hair cell loss results in secondary regression of peripheral auditory fibers (PAFs) and loss of spiral ganglion neurons (SGNs). The performance of cochlear implants (CI) in rehabilitating hearing depends on survival of SGNs. Here we compare the effects of adeno-associated virus vectors with neurotrophin gene inserts, AAV.BDNF and AAV.Ntf3, on guinea pig ears deafened systemically (kanamycin and furosemide) or locally (neomycin). AAV.BDNF or AAV.Ntf3 was delivered to the guinea pig cochlea one week following deafening and ears were assessed morphologically 3 months later. At that time, neurotrophins levels were not significantly elevated in the cochlear fluids, even though in vitro and shorter term in vivo experiments demonstrate robust elevation of neurotrophins with these viral vectors. Nevertheless, animals receiving these vectors exhibited considerable re-growth of PAFs in the basilar membrane area. In systemically deafened animals there was a negative correlation between the presence of differentiated supporting cells and PAFs, suggesting that supporting cells influence the outcome of neurotrophin over-expression aimed at enhancing the cochlear neural substrate. Counts of SGN in Rosenthal's canal indicate that BDNF was more effective than NT-3 in preserving SGNs. The results demonstrate that a transient elevation in neurotrophin levels can sustain the cochlear neural substrate in the long term.