Neurotrophin-3 regulates ribbon synapse density in the cochlea and induces synapse regeneration after acoustic trauma.
Neurotrophin-3 regulates ribbon synapse density in the cochlea and induces synapse regeneration after acoustic trauma.
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DOI：
10.7554/elife.03564
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发表时间：
2014-10-20
期刊：
影响因子：
7.7
通讯作者：
Corfas G
中科院分区：
文献类型：
--
作者：
Wan G;Gómez-Casati ME;Gigliello AR;Liberman MC;Corfas G
神经营养因子-3 （Ntf3）和脑源性神经营养因子（Bdnf）对胚胎内耳感觉神经元的存活和神经元向感觉上皮的投射的建立至关重要，但它们的出生后功能尚不清楚。通过对小鼠进行细胞特异性诱导基因重组，我们发现，在出生后的内耳中，Bbnf和Ntf3分别是前庭和耳蜗上皮毛细胞带突触形成和维持所必需的。我们还表明，这些上皮中的支持细胞是神经营养因子的关键内源性来源。利用嵌合表达的新毛细胞CreERT细胞系，我们还发现Ntf3对耳蜗突触发生的影响是高度局部的。此外，支持细胞来源的Ntf3，而不是Bbnf，促进耳蜗功能的恢复和带状突触的再生。这些结果表明，胶质源性神经营养因子在内耳突触密度和损伤后突触再生中起重要作用。DOI: http://dx.doi.org/10.7554/eLife.03564.001噪音引起的听力损失很常见，可能是由于长期暴露在中等水平的噪音中而不被认为是痛苦甚至不愉快的。一些听力损失可归因于内耳中称为耳蜗的部分毛细胞的死亡。当声波击中耳蜗时，它们会引起耳蜗内的液体振动：毛细胞检测到这些振动并将其转化为电信号，沿着神经元发送到大脑。然而，过于强烈的振动会破坏毛细胞。越来越多的证据表明，听力损失也是耳蜗中连接毛细胞和神经元的突触受损造成的。在内耳的发育过程中，需要一种叫做生长因子的分子来确保这些神经元的存活。Wan等人预测，这些生长因子可能在成年动物中也有作用，产生更多的生长因子可能有助于保护听力免受噪音的破坏性影响。与此一致的是，经过基因改造，缺乏一种叫做神经营养因子-3的生长因子的老鼠，与对照组老鼠相比，耳蜗不能正常工作，毛细胞和神经元之间的突触也更少。相反，产生过多神经营养素-3的小鼠比对照组有更多的突触，并且从暴露在100分贝噪音（大约是风钻的音量）中2小时的影响中恢复得更快。对耳蜗的研究表明，额外的神经营养素-3促进了被噪音损坏的突触的再生。当噪声暴露后不久开始过量生产时，神经营养因子-3的有益作用仍然可见，这表明它可能具有治疗潜力。最近有证据表明，在与年龄有关的听力损失和噪音引起的听力损失中，突触的丧失往往发生在毛细胞死亡之前，这一点尤为重要。DOI: http://dx.doi.org/10.7554/eLife.03564.002
Neurotrophin-3 (Ntf3) and brain derived neurotrophic factor (Bdnf) are critical for sensory neuron survival and establishment of neuronal projections to sensory epithelia in the embryonic inner ear, but their postnatal functions remain poorly understood. Using cell-specific inducible gene recombination in mice we found that, in the postnatal inner ear, Bbnf and Ntf3 are required for the formation and maintenance of hair cell ribbon synapses in the vestibular and cochlear epithelia, respectively. We also show that supporting cells in these epithelia are the key endogenous source of the neurotrophins. Using a new hair cell CreERT line with mosaic expression, we also found that Ntf3's effect on cochlear synaptogenesis is highly localized. Moreover, supporting cell-derived Ntf3, but not Bbnf, promoted recovery of cochlear function and ribbon synapse regeneration after acoustic trauma. These results indicate that glial-derived neurotrophins play critical roles in inner ear synapse density and synaptic regeneration after injury. DOI: http://dx.doi.org/10.7554/eLife.03564.001 Noise-induced hearing loss is common, and can result from prolonged exposure to moderate levels of noise that are not perceived as painful or even unpleasant. Some hearing loss can be attributed to the death of hair cells in a part of the inner ear called the cochlea. When sound waves hit the cochlea, they cause the fluid inside it to vibrate: the hair cells detect these vibrations and convert them into electrical signals that are sent along neurons to the brain. However, vibrations that are too strong can destroy hair cells. Increasing evidence suggests that hearing loss also results from damage to the synapses that connect the hair cells and the neurons in the cochlea. During development of the inner ear, molecules called growth factors are needed to ensure the survival of these neurons. Wan et al. predicted that these growth factors might also have a role in adult animals, and that producing more of them might help to safeguard hearing from the damaging effects of noise. Consistent with this, mice that were genetically modified to lack a growth factor called neurotrophin-3 had cochleae that did not work properly and had fewer synapses between hair cells and neurons compared to control mice. Conversely, mice that produced too much neurotrophin-3 had more synapses than controls and also recovered more quickly from the effects of 2 hr exposure to 100 dB noise (roughly the volume of a pneumatic drill). Studies of the cochlea revealed that the extra neurotrophin-3 had boosted the regeneration of synapses damaged by the noise. The beneficial effects of neurotrophin-3 were still seen when overproduction was started shortly after noise exposure, suggesting that it could have therapeutic potential. This is particularly significant in the light of recent evidence that the loss of synapses often comes before the death of hair cells in both age-related hearing loss and noise-induced hearing loss. DOI: http://dx.doi.org/10.7554/eLife.03564.002