Glueckert R, Wietzorrek G, Kammen-Jolly K, Scholtz A, Stephan K, Striessnig J, Schrott-Fischer A
Universitätsklinik für Hals-, Nasen und Ohrenheilkunde, Anichstr. 35, A-6020, Innsbruck, Austria.
Hear Res. 2003 Apr;178(1-2):95-105. doi: 10.1016/s0378-5955(03)00054-6.
Voltage-gated Ca(2+) channels formed by subunits (class D Ca(2+) channels) tightly regulate neurotransmitter release from cochlear inner hair cells (IHCs) by controlling the majority of depolarisation-induced Ca(2+) entry. We have recently shown that the absence of these channels can cause deafness and degeneration of outer hair cells (OHCs) and IHCs in alpha1D-deficient mice (alpha1D(-/-)) (Platzer et al., 2000. Cell 102, 89-97). We investigated the time-dependent patterns of degeneration during postnatal development in the alpha1D(-/-) mouse cochlea using light and electron microscopy. At postnatal day 3 (P3), electron microscopy revealed no morphological aberrations in sensory cells, in afferent as well as in efferent nerve endings. But at P7 we observed a beginning degeneration of afferent nerve fibres by electron microscopy. By P15, we found a loss of OHCs in apical turns but electron microscopy revealed no ultrastructural changes in IHCs and efferent axons as compared to C57 black control animals (C57BL). We demonstrated by serial ultrathin sectioning of 15 days old alpha1D(-/-) mice that intact efferent nerve fibres formed direct contacts with IHCs as the degeneration of afferent nerve fibres progressed. We also saw a notable degeneration of spiral ganglion cells at P15. By 8 months, nearly all spiral ganglion and sensory cells of the organ of Corti were absent. Random ultrathin sectioning gave the impression that synaptic bodies abundant in wild-type animals were absent in nearly all alpha1D(-/-) mice investigated. We conclude that besides presumably reduced synaptic bodies the absence of class D L-type Ca(2+) channels does not prevent morphological development of the cochlea until P3 but may cause cochlear degeneration thereafter. The observed pattern of degeneration involves afferent nerve fibres (P7) followed by cell bodies in the spiral ganglion (P15), OHCs (P15) and IHCs (after P15).
由亚基构成的电压门控性Ca(2+)通道（D类Ca(2+)通道）通过控制大部分去极化诱导的Ca(2+)内流，紧密调节耳蜗内毛细胞（IHC）的神经递质释放。我们最近发现，这些通道的缺失会导致α1D缺陷小鼠（α1D(-/-)）出现耳聋以及外毛细胞（OHC）和内毛细胞退化（Platzer等人，2000年。《细胞》102卷，89 - 97页）。我们使用光学显微镜和电子显微镜研究了α1D(-/-)小鼠耳蜗出生后发育过程中随时间变化的退化模式。出生后第3天（P3），电子显微镜显示感觉细胞、传入神经末梢和传出神经末梢均无形态异常。但在P7时，电子显微镜观察到传入神经纤维开始退化。到P15时，我们发现顶端螺旋的OHC缺失，但与C57黑色对照动物（C57BL）相比，电子显微镜显示IHC和传出轴突无超微结构变化。通过对15日龄α1D(-/-)小鼠进行连续超薄切片，我们证明随着传入神经纤维退化，完整的传出神经纤维与IHC形成了直接接触。我们还在P15时观察到螺旋神经节细胞明显退化。到8个月时，柯蒂氏器的几乎所有螺旋神经节和感觉细胞都消失了。随机超薄切片显示，在几乎所有研究的α1D(-/-)小鼠中，野生型动物中丰富的突触小体都不存在。我们得出结论，除了可能减少的突触小体之外，D类L型Ca(2+)通道的缺失在P3之前不会阻止耳蜗的形态发育，但此后可能会导致耳蜗退化。观察到的退化模式包括传入神经纤维（P7），随后是螺旋神经节中的细胞体（P15）、OHC（P15）和IHC（P15之后）。
