Department of Biomedical Science, University of Sheffield, Sheffield, United Kingdom.
PLoS One. 2012;7(2):e31433. doi: 10.1371/journal.pone.0031433. Epub 2012 Feb 14.
Down syndrome is one of the most common congenital disorders leading to a wide range of health problems in humans, including frequent otitis media. The Tc1 mouse carries a significant part of human chromosome 21 (Hsa21) in addition to the full set of mouse chromosomes and shares many phenotypes observed in humans affected by Down syndrome with trisomy of chromosome 21. However, it is unknown whether Tc1 mice exhibit a hearing phenotype and might thus represent a good model for understanding the hearing loss that is common in Down syndrome. In this study we carried out a structural and functional assessment of hearing in Tc1 mice. Auditory brainstem response (ABR) measurements in Tc1 mice showed normal thresholds compared to littermate controls and ABR waveform latencies and amplitudes were equivalent to controls. The gross anatomy of the middle and inner ears was also similar between Tc1 and control mice. The physiological properties of cochlear sensory receptors (inner and outer hair cells: IHCs and OHCs) were investigated using single-cell patch clamp recordings from the acutely dissected cochleae. Adult Tc1 IHCs exhibited normal resting membrane potentials and expressed all K(+) currents characteristic of control hair cells. However, the size of the large conductance (BK) Ca(2+) activated K(+) current (I(K,f)), which enables rapid voltage responses essential for accurate sound encoding, was increased in Tc1 IHCs. All physiological properties investigated in OHCs were indistinguishable between the two genotypes. The normal functional hearing and the gross structural anatomy of the middle and inner ears in the Tc1 mouse contrast to that observed in the Ts65Dn model of Down syndrome which shows otitis media. Genes that are trisomic in Ts65Dn but disomic in Tc1 may predispose to otitis media when an additional copy is active.
唐氏综合征是最常见的先天性疾病之一，可导致人类出现广泛的健康问题，包括频繁的中耳炎。除了全套的小鼠染色体外，Tc1 小鼠还携带人类染色体 21 号（Hsa21）的重要部分，并且与 21 号染色体三体的唐氏综合征患者表现出许多相同的表型。然而，目前尚不清楚 Tc1 小鼠是否表现出听力表型，因此它可能是一个很好的模型，可用于了解唐氏综合征患者常见的听力损失。在这项研究中，我们对 Tc1 小鼠的听力进行了结构和功能评估。与同窝对照相比，Tc1 小鼠的听觉脑干反应（ABR）测量值显示正常阈值，ABR 波形潜伏期和幅度与对照相同。中耳和内耳的大体解剖结构在 Tc1 和对照小鼠之间也相似。通过对急性分离的耳蜗进行单细胞膜片钳记录，研究了耳蜗感觉感受器（内毛细胞和外毛细胞：IHC 和 OHC）的生理特性。成年 Tc1 IHC 表现出正常的静息膜电位，并表达了所有特征性的控制毛细胞的 K+电流。然而，大电导（BK）Ca2+激活的 K+电流（I（K，f））的大小增加，该电流可使快速的电压反应成为可能，这对于准确的声音编码至关重要，在 Tc1 IHC 中增大。两种基因型之间的 OHC 所有生理特性均无差异。与 Ts65Dn 模型（其表现为中耳炎）相比，Tc1 小鼠具有正常的功能性听力和中耳和内耳的大体结构解剖结构。在 Ts65Dn 中三体的基因，但在 Tc1 中为二体的基因可能会导致在额外的基因拷贝活跃时易发生中耳炎。
