Cochlear Neurotrophin-3 overexpression at mid-life prevents age-related inner hair cell synaptopathy and slows age-related hearing loss.
Cochlear Neurotrophin-3 overexpression at mid-life prevents age-related inner hair cell synaptopathy and slows age-related hearing loss.
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年龄相关性听力损失（ARHL）是老年人最常见的感觉障碍。这种进行性病理学通常具有心理和医学共病，包括社会孤立，抑郁和认知能力下降。尽管ARHL具有巨大的社会和经济影响，但目前还没有预防或减缓其进展的疗法。内毛细胞（IHC）和螺旋神经节神经元（SGN）之间的突触丢失，也称为IHC突触病是耳蜗老化的早期事件，先于神经元和毛细胞损失。为了确定是否可以预防年龄相关的IHC突触病，以及这是否会影响ARHL的时间进程，我们测试了从中年开始耳蜗神经营养素-3（Ntf 3）过表达的影响。我们选择Ntf 3是因为这种神经营养因子在新生儿期调节IHC-SGN突触的形成。我们现在表明，与年龄匹配的对照组相比，从中年开始通过IHC支持细胞触发Ntf 3过表达迅速增加了声音诱发神经电位的幅度，表明Ntf 3在病理学最小时对耳蜗功能产生积极影响。此外，与年龄匹配的对照组相比，在寿命接近尾声时，Ntf 3过表达小鼠的ARHL较轻，沿听觉上行通路的声诱发电位沿着增大，IHC突触病减少。我们的研究结果还提供了证据，表明耳蜗Ntf 3表达的年龄相关性降低有助于ARHL，并且Ntf 3补充剂可以作为这种流行疾病的治疗方法。此外，这些研究结果表明，在发育过程中调节突触发生的因素可以预防大脑中与年龄相关的突触病，这是一种涉及几种中枢神经系统退行性疾病的过程。我们发现，在中年开始触发耳蜗Ntf 3过表达迅速增加了声音诱发神经电位的幅度，并减少了与年龄相关的内毛细胞突触丢失。因此，在寿命接近尾声时，Ntf 3过表达小鼠具有较轻的年龄相关性听力损失，并沿听觉上行通路保持较大的声诱发电位沿着。这些发现提供了证据表明，Ntf 3补充剂可以作为这种流行疾病的治疗方法。
Age‐related hearing loss (ARHL) is the most prevalent sensory deficit in the elderly. This progressive pathology often has psychological and medical comorbidities, including social isolation, depression, and cognitive decline. Despite ARHL's enormous societal and economic impact, no therapies to prevent or slow its progression exist. Loss of synapses between inner hair cells (IHCs) and spiral ganglion neurons (SGNs), a.k.a. IHC synaptopathy, is an early event in cochlear aging, preceding neuronal and hair cell loss. To determine if age‐related IHC synaptopathy can be prevented, and if this impacts the time‐course of ARHL, we tested the effects of cochlear overexpression of neurotrophin‐3 (Ntf3) starting at middle age. We chose Ntf3 because this neurotrophin regulates the formation of IHC‐SGN synapses in the neonatal period. We now show that triggering Ntf3 overexpression by IHC supporting cells starting in middle age rapidly increases the amplitude of sound‐evoked neural potentials compared with age‐matched controls, indicating that Ntf3 produces a positive effect on cochlear function when the pathology is minimal. Furthermore, near the end of their lifespan, Ntf3‐overexpressing mice have milder ARHL, with larger sound‐evoked potentials along the ascending auditory pathway and reduced IHC synaptopathy compared with age‐matched controls. Our results also provide evidence that an age‐related decrease in cochlear Ntf3 expression contributes to ARHL and that Ntf3 supplementation could serve as a therapeutic for this prevalent disorder. Furthermore, these findings suggest that factors that regulate synaptogenesis during development could prevent age‐related synaptopathy in the brain, a process involved in several central nervous system degenerative disorders. We show that triggering cochlear Ntf3 overexpression starting in middle age rapidly increases the amplitude of sound‐evoked neural potentials and reduces age‐related inner hair cells synapse loss. Thus, near the end of their lifespan, Ntf3‐overexpressing mice have milder age‐related hearing loss and maintain larger sound‐evoked potentials along the ascending auditory pathway. These findings provide evidence that Ntf3 supplementation could serve as a therapeutic for this prevalent disorder.
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影响因子：
7.7
作者：
Wan G;Gómez-Casati ME;Gigliello AR;Liberman MC;Corfas G
通讯作者：
Corfas G
影响因子：
5.3
作者：
Kujawa, SG;Liberman, MC
通讯作者：
Liberman, MC
影响因子：
3.6
作者：
Knipper, M;Zimmermann, U;Zenner, HP
通讯作者：
Zenner, HP
影响因子：
2.8
作者：
Stankovic, KM;Corfas, G
通讯作者：
Corfas, G
DOI：
10.1523/jneurosci.2845-09.2009
发表时间：
2009-11-11
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Kujawa SG;Liberman MC
通讯作者：
Liberman MC