Mechanisms for the hearing loss in sphingomyelin synthase-1deficient mice

鞘磷脂（SM）是一种鞘脂，据报道作为质膜的结构成分并参与信号转导。SM代谢在听力过程中的作用仍有争议。在这里，我们研究了SM合成酶（SMS）在听觉功能中的作用，它被细分为家族成员SMS1和SMS2。听觉脑干反应（ABR）的测量显示SMS1-/-小鼠在低频范围（4-16 kHz）存在听力损伤。作为这种损伤的可能机制，我们发现这些小鼠的血管纹（SV）表现出萎缩和边缘细胞紊乱。因此，SMS1-/-小鼠表现出明显较小的耳蜗电位（EPs）。作为EP减少的可能机制，我们发现SMS1-/-小鼠SV中KCNQ1通道蛋白的表达模式改变和水平降低。这些小鼠的耳声发射失真程度也有所降低。定量比较耳蜗尖部和基底部的SV萎缩、KCNQ1表达和外毛细胞密度，结果显示无位置依赖性，但在耳蜗尖部观察到的巨噬细胞入侵SV比基底部多，提示耳蜗位置依赖性氧化应激在SMS1-/-小鼠听力损失的频率依赖性中起作用。随着年龄的增长，SMS1-/-小鼠的ABR阈值升高、EPs下降和KCNQ1表达模式异常均呈进行性变化。然而，缺乏SMS2的小鼠既没有表现出可检测到的听力损失，也没有表现出EPs的变化。综上所述，我们的研究结果表明，听力损伤发生在SMS1-/小鼠身上，而不是SMS2-/小鼠身上。SV缺陷和随后的EPs减少可能至少部分解释了SMS1-/-小鼠的听力损伤。

Sphingomyelin (SM) is a sphingolipid reported to function as astructural component of plasma membranes and to participate in signal transduction.The role of SM metabolism in the process of hearing remains controversial. Here, weexamined the role of SM synthase (SMS), which is subcategorized into the familymembers SMS1 and SMS2, in auditory function. Measurements of auditory brainstemresponse (ABR) revealed hearing impairment in SMS1-/-mice in a low frequency range(4-16 kHz). As a possible mechanism of this impairment, we found that the striavascularis (SV) in these mice exhibited atrophy and disorganized marginal cells.Consequently , SMS1-/-mice exhibited significantly smaller endocochlear potentials(EPs). As a possible mechanism for EP reduction, we found altered expression patternsand a reduced level of KCNQ1 channel protein in the SV of SMS1-/-mice. These micealso exhibited reduced levels of distortion product otoacoustic emissions. Quantitativecomparison of the SV atrophy , KCNQ1 expression, and outer hair cell density at thecochlear apical and basal turns revealed no location-dependence, but more macrophageinvasion into the SV was observed in the apical region than the basal region,suggesting a role of cochlear location-dependent oxidative stress in producing thefrequency-dependence of hearing loss in SMS1-/-mice. Elevated ABR thresholds,decreased EPs, and abnormal KCNQ1 expression patterns in SMS1-/-mice were allfound to be progressive with age. Mice lacking SMS2, however , exhibited neitherdetectable hearing loss nor changes in their EPs. Taken together , our results suggestthat hearing impairments occur in SMS1-/-but not SMS2-/-mice. Defects in the SV withsubsequent reductions in EPs may account, at least partially , for hearing impairmentsin SMS1-/-mice.