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

鞘磷脂是一种神经鞘磷脂，被认为是质膜的非结构成分并参与信号转导，但其代谢在听力过程中的作用仍存在争议。在这里，我们研究了SM合成酶(SM Synthase，SMS)在听觉功能中的作用。SM合成酶分为SMS1和SMS2两个亚类。听性脑反应(ABR)测试显示，SMS1-/-小鼠在低频范围(4-16 kHz)有听力障碍。作为这种损伤的可能机制，我们发现这些小鼠的纹状血管(SV)出现萎缩和边缘细胞紊乱。因此，SMS1-/-小鼠的耳蜗内电位(EPs)显著降低。作为EP减少的一种可能机制，我们在SMS1-/-小鼠的SV中发现了表达模式的改变和KCNQ1通道蛋白的降低。这些小鼠的失真产物耳声发射水平也有所降低。SMS1-/-小鼠耳蜗尖、基转区SV萎缩、KCNQ1表达和外毛细胞密度的定量比较无位置依赖性，但顶区比基底区有更多巨噬细胞侵入SV，提示耳蜗区位置依赖性氧化应激在SMS1-/-小鼠听力损失的频率依赖性产生中起作用。在SMS1-/-小鼠中，ABR阈值升高、EPs降低和KCNQ1异常表达模式都被发现是随着年龄的增长而递增的。然而，缺乏SMS2的小鼠既没有表现出明显的听力损失，也没有表现出EPs的变化。综上所述，我们的结果表明，SMS1-/-小鼠存在听力障碍，但SMS2-/-小鼠没有。在SMS1-/-小鼠中，SV的缺陷和随后的EPs的减少可能至少部分地解释了听力损伤。

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.