Mice heterozygous for the Cdh23/Ahl1 mutation show age-related deficits in auditory temporal processing
Mice heterozygous for the Cdh23/Ahl1 mutation show age-related deficits in auditory temporal processing
复制标题
DOI：
10.1016/j.neurobiolaging.2019.02.029
复制
发表时间：
2019-09-01
影响因子：
4.2
通讯作者：
Oliver, Douglas L.
中科院分区：
文献类型：
--
作者：
Burghard, Alice L.;Morel, Nazli P.;Oliver, Douglas L.
Cdh 23基因突变与人类综合征性和非综合征性听力损失以及C57 BL/6小鼠的年龄相关性听力损失有关。一般认为，人类患者（以及小鼠模型）只有在突变是纯合的情况下才具有听力损失表型。然而，听力残疾患者的一个主要抱怨是言语清晰度降低，这可能与时间处理缺陷有关，而不仅仅是阈值升高。在这项研究中，我们使用振幅调制跟随反应（AMFR）来测试Cdh 23（735 A）（> G）杂合子小鼠是否具有包括时间处理缺陷的听觉表型。将Cdh 2 - 3（735 A）（> G）突变杂合小鼠的听力与2-3、6和12月龄的3组两种性别小鼠中的突变或野生型纯合小鼠的年龄匹配小鼠进行比较。AMFR技术用于在所有小鼠的听力范围内产生客观听力阈值，并测试其时间处理。我们发现在5-11周龄的突变纯合子小鼠中存在基因型依赖性听力损失，该年龄段的C57 BL/6背景小鼠通常被认为具有正常听力。杂合子动物保持正常的听力阈值长达一岁。然而，杂合子动物在一岁时表现出时间处理能力的下降，这与它们的听力阈值无关。这些结果表明，Cdh 23突变杂合子小鼠没有真正正常的听力。(C)2019爱思唯尔公司All rights reserved.
A mutation in the Cdh23 gene is implicated in both syndromic and nonsyndromic hearing loss in humans and age-related hearing loss in C57BL/6 mice. It is generally assumed that human patients (as well as mouse models) only have a hearing loss phenotype if the mutation is homozygous. However, a major complaint for patients with a hearing disability is a reduced speech intelligibility that may be related to temporal processing deficits rather than just elevated thresholds. In this study, we used the amplitude modulation following response (AMFR) to test whether mice heterozygous for Cdh23(735A) (> G) have an auditory phenotype that includes temporal processing deficits. The hearing of mice heterozygous for the Cdh23(735A) (> G) mutation was compared with age-matched mice homozygous for either the mutation or the wild type in 3 cohorts of mice of both sexes at 2-3, 6, and 12 months of age. The AMFR technique was used to generate objective hearing thresholds for all mice across their range of hearing and to test their temporal processing. We found a genotype-dependent hearing loss in mice homozygous for the mutation starting at 5-11 weeks of age, an age when mice on the C57BL/6 background are often presumed to have normal hearing. The heterozygous animals retained normal hearing thresholds up to one year of age. Nevertheless, the heterozygous animals showed a decline in temporal processing abilities at one year of age that was independent of their hearing thresholds. These results suggest that mice heterozygous for the Cdh23 mutation do not have truly normal hearing. (C) 2019 Elsevier Inc. All rights reserved.