Central auditory processing disorder (CAPD) is associated with difficulties hearing and processing acoustic information, as well as subsequent impacts on the development of higher-order cognitive processes (i.e., attention and language). Yet CAPD also lacks clear and consistent diagnostic criteria, with widespread clinical disagreement on this matter. As such, identification of biological markers for CAPD would be useful. A recent genome association study identified a potential CAPD risk gene, USH2A. In a homozygous state, this gene is associated with Usher syndrome type 2 (USH2), a recessive disorder resulting in bilateral, high-frequency hearing loss due to atypical cochlear hair cell development. However, children with heterozygous USH2A mutations have also been found to show unexpected low-frequency hearing loss and reduced early vocabulary, contradicting assumptions that the heterozygous (carrier) state is “phenotype free”. Parallel evidence has confirmed that heterozygous Ush2a mutations in a transgenic mouse model also cause low-frequency hearing loss (Perrino et al., 2020). Importantly, these auditory processing anomalies were still evident after covariance for hearing loss, suggesting a CAPD profile. Since usherin anomalies occur in the peripheral cochlea and not central auditory structures, these findings point to upstream developmental feedback effects of peripheral sensory loss on high-level processing characteristic of CAPD. In this study, we aimed to expand upon the mouse behavioral battery used in Perrino et al. (2020) by evaluating central auditory brain structures, including the superior olivary complex (SOC) and medial geniculate nucleus (MGN), in heterozygous and homozygous Ush2a mice. We found that heterozygous Ush2a mice had significantly larger SOC volumes while homozygous Ush2a had significantly smaller SOC volumes. Heterozygous mutations did not affect the MGN; however, homozygous Ush2a mutations resulted in a significant shift towards more smaller neurons. These findings suggest that alterations in cochlear development due to USH2A variation can secondarily impact the development of brain regions important for auditory processing ability.

中文翻译：

---

USH2A的外围异常在Usher综合征和CAPD的小鼠模型中引起中央听觉异常

中枢听觉处理障碍（CAPD）与听力和处理声学信息的困难以及对高级认知过程（即注意力和语言）发展的后续影响有关。然而，CAPD也缺乏明确和一致的诊断标准，在此问题上存在广泛的临床分歧。这样，鉴定CAPD的生物标记将是有用的。最近的基因组关联研究确定了潜在的CAPD风险基因USH2A。在纯合状态下，该基因与2型Usher综合征（USH2）相关，这是一种隐性疾病，由于非典型的耳蜗毛细胞发育，导致双侧高频听力丧失。但是，杂合子USH2A患儿还发现突变显示出意外的低频听力损失和减少的早期词汇，这与杂合（携带者）状态是“无表型”的假设相矛盾。平行证据已证实，转基因小鼠模型中的杂合Ush2a突变也会引起低频听力丧失（Perrino等，2020）。重要的是，在听力损失发生协方差后，这些听觉处理异常仍然很明显，这提示了CAPD的特征。由于usherin异常发生在周围的耳蜗而不是在中央听觉结构中，这些发现指出了周围感觉丧失对CAPD高级处理特征的上游发育反馈作用。在这项研究中，我们旨在扩展Perrino等人使用的鼠标行为电池。（2020）通过评估杂合和纯合Ush2a小鼠的中央听觉大脑结构，包括上橄榄叶复合体（SOC）和内侧膝状核（MGN）。我们发现，杂USH2A小鼠有显著更大的SOC量而纯合子USH2A有显著较小的SOC卷。杂合子突变不影响MGN。但是，纯合子Ush2a突变导致向更小的神经元的重大转变。这些发现表明，由于USH2A变异而引起的耳蜗发育改变可继而影响对听觉处理能力很重要的大脑区域的发育。