Noise-induced plasticity of KCNQ2/3 and HCN channels underlies vulnerability and resilience to tinnitus.
Noise-induced plasticity of KCNQ2/3 and HCN channels underlies vulnerability and resilience to tinnitus.
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DOI：
10.7554/elife.07242
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发表时间：
2015-08-27
期刊：
影响因子：
7.7
通讯作者：
Tzounopoulos T
中科院分区：
文献类型：
--
作者：
Li S;Kalappa BI;Tzounopoulos T
噪声性耳鸣易感性与耳蜗背核主要神经元梭形细胞自发放电频率增加有关。这种活动过度至少部分是由Kv7.2/3（KCNQ2/3）钾电流降低引起的。然而，耳鸣恢复力的生物物理机制仍然未知，这是在暴露于噪音的小鼠中观察到的，但没有发生耳鸣（非耳鸣小鼠）。我们的研究结果表明，噪声暴露诱导，平均而言，减少KCNQ2/3通道活动的梭形细胞在噪声暴露后4天暴露的小鼠。在接下来的3天内不能补偿这种减少的小鼠中会产生Tinaldehyde。在显示KCNQ 2/3通道活性重新出现和HCN通道活性降低的小鼠中，对耳鸣的恢复力得以发展。我们的研究结果突出了KCNQ2/3和HCN通道作为设计新疗法的潜在靶点，可以促进耳鸣的恢复。耳鸣通常被描述为"耳鸣"。虽然在没有任何真正的外部噪音的情况下听到的幻声可以采取各种形式，包括嗡嗡声，口哨声或嗡嗡声。虽然训练大脑不太注意这些内部产生的声音有时可以减少耳鸣的影响，但许多人发现这种疾病会显着降低他们的生活质量。耳鸣的主要原因之一是长期或反复暴露在过量的噪音中。然而，并不是每个人都有这样的接触发展耳鸣。有些人似乎表现出天生的适应力。确定这种弹性的基础可以开发增强这些机制的药物，从而将这种保护扩展到那些否则会有耳鸣风险的人。Li等人通过研究小鼠的耳鸣恢复机制，使这一点更近了一步。同一个研究小组先前的研究显示，耳鸣小鼠脑干中一组被称为“梭形细胞”的神经元过度活跃。这些细胞直接从耳朵接收输入，它们的活动过度主要是由于称为KCNQ 2/3通道的离子通道不太活跃。这些通道允许钾离子流过膜，从而控制梭形细胞的活性。Li等人现在表明，暴露于过量噪音会导致暴露小鼠的KCNQ 2/3活性降低。然而，在成功避免耳鸣的动物中，KCNQ 2/3活性在几天内自发恢复。这种恢复触发另一种类型的离子通道（称为HCN通道）的活性降低。KCNQ和HCN通道的组合灵活性防止梭形细胞中耳鸣相关的过度活跃。因此，增加KCNQ2/3通道活性和/或降低HCN通道活性的药物可以提高耳鸣的恢复力。在未来，同时针对两种通道类型可以提供一种有效的治疗方法，副作用最小。DOI：www.example.com网站
Vulnerability to noise-induced tinnitus is associated with increased spontaneous firing rate in dorsal cochlear nucleus principal neurons, fusiform cells. This hyperactivity is caused, at least in part, by decreased Kv7.2/3 (KCNQ2/3) potassium currents. However, the biophysical mechanisms underlying resilience to tinnitus, which is observed in noise-exposed mice that do not develop tinnitus (non-tinnitus mice), remain unknown. Our results show that noise exposure induces, on average, a reduction in KCNQ2/3 channel activity in fusiform cells in noise-exposed mice by 4 days after exposure. Tinnitus is developed in mice that do not compensate for this reduction within the next 3 days. Resilience to tinnitus is developed in mice that show a re-emergence of KCNQ2/3 channel activity and a reduction in HCN channel activity. Our results highlight KCNQ2/3 and HCN channels as potential targets for designing novel therapeutics that may promote resilience to tinnitus. DOI: http://dx.doi.org/10.7554/eLife.07242.001 Tinnitus is often described as ‘ringing in the ears’. Though the phantom sounds, which are heard in the absence of any genuine external noise, can take a variety of forms including buzzing, whistling, or humming. While training the brain to pay less attention to these internally generated sounds can sometimes reduce the impact of tinnitus, many people find that the disorder reduces their quality of life significantly. One of the main causes of tinnitus is prolonged or repeated exposure to excessive noise. However, not everyone with such exposure develops tinnitus. Certain individuals appear to show a natural resilience. Identifying the basis of this resilience could make it possible to develop drugs that enhance these mechanisms, and thereby extend this protection to those who would otherwise be at risk of tinnitus. Li et al. have brought this a step closer by studying tinnitus resilience mechanisms in mice. Previous work by the same group revealed that in mice with tinnitus a group of neurons in the brainstem called ‘fusiform cells’ are overly active. These cells receive direct input from the ear, and their hyperactivity is largely due to ion channels called KCNQ2/3 channels being less active. These channels allow for potassium ions to flow across the membrane and thereby control the activity of fusiform cells. Li et al. now show that exposure to excessive noise causes a reduction in KCNQ2/3 activity in the exposed mice. However, in animals that successfully avoid developing tinnitus, KCNQ2/3 activity spontaneously recovers over the course of a few days. This recovery triggers a reduction in the activity of another type of ion channel, known as the HCN channel. The combined flexibility of KCNQ and HCN channels prevents tinnitus-associated hyperactivity in the fusiform cells. Drugs that increase activity of KCNQ2/3 channels, and/or reduce activity of HCN channels, could thus boost resilience to tinnitus. In the future, targeting both channel types at the same time could provide an effective treatment with minimal side effects. DOI: http://dx.doi.org/10.7554/eLife.07242.002