Maturation of Ribbon Synapses in Hair Cells Is Driven by Thyroid Hormone
Maturation of Ribbon Synapses in Hair Cells Is Driven by Thyroid Hormone
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DOI：
10.1523/jneurosci.3974-06.2007
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发表时间：
2007-03
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影响因子：
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通讯作者：
Gaston Sendin;A. Bulankina;D. Riedel;T. Moser
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作者：
Gaston Sendin;A. Bulankina;D. Riedel;T. Moser
内毛细胞 (IHC) 的带状突触经历发育成熟，直到听力出现后。在这里，我们研究了 IHC 突触发生是否受甲状腺激素 (TH) 调节。我们对无甲状腺和 TH 取代的 Pax8−/− 小鼠在出生后发育过程中的 IHC 中的 Ca2+ 电流和胞吐膜电容变化进行了穿孔膜片钳记录。在出生后第二周结束时，无甲状腺 IHC 中的 Ca2+ 电流仍然升高，而野生型和 TH 拯救的突变型 IHC 中的 Ca2+ 电流则在发育过程中下降。在无甲状腺 IHC 中，Ca2+ 流入触发易释放囊泡池胞吐作用的效率降低。尽管 TH 缺乏，但带状突触还是形成了。然而，与野生型不同的是，在野生型中，突触消除大约在听力开始时发生，在 2 周龄的无甲状腺 IHC 中，带状突触的数量仍然较高。此外，这些突触的超微结构显得不成熟。使用定量逆转录 PCR，我们发现 Corti 器官中神经元 SNARE（可溶性 N-乙基马来酰亚胺敏感因子附着蛋白受体）蛋白、SNAP25（25 kDa 突触体相关蛋白）和突触短蛋白 1 的 mRNA 存在 TH 依赖性发育上调。这些分子变化可能有助于提高成熟 IHC 的胞吐效率。 2 周龄无甲状腺 Pax8−/− 小鼠的 IHC 维持了正常的暂时传出神经支配。此外，它们缺乏大电导Ca2+激活的K+通道和KCNQ4通道。这与持续增加的 Ca2+ 流入一起允许持续产生动作电位。我们得出结论，TH 调节 IHC 分化，并且对于带状突触的形态和功能成熟至关重要。我们认为 IHC 的突触前功能障碍是先天性甲状腺功能减退性耳聋的一种机制。
Ribbon synapses of inner hair cells (IHCs) undergo developmental maturation until after the onset of hearing. Here, we studied whether IHC synaptogenesis is regulated by thyroid hormone (TH). We performed perforated patch-clamp recordings of Ca2+ currents and exocytic membrane capacitance changes in IHCs of athyroid and TH-substituted Pax8−/− mice during postnatal development. Ca2+ currents remained elevated in athyroid IHCs at the end of the second postnatal week, when it had developmentally declined in wild-type and TH-rescued mutant IHCs. The efficiency of Ca2+ influx in triggering exocytosis of the readily releasable vesicle pool was reduced in athyroid IHCs. Ribbon synapses were formed despite the TH deficiency. However, different from wild type, in which synapse elimination takes place at approximately the onset of hearing, the number of ribbon synapses remained elevated in 2-week-old athyroid IHCs. Moreover, the ultrastructure of these synapses appeared immature. Using quantitative reverse transcription-PCR, we found a TH-dependent developmental upregulation of the mRNAs for the neuronal SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins, SNAP25 (synaptosomal-associated protein of 25 kDa) and synaptobrevin 1, in the organ of Corti. These molecular changes probably contribute to the improvement of exocytosis efficiency in mature IHCs. IHCs of 2-week-old athyroid Pax8−/− mice maintained the normally temporary efferent innervation. Moreover, they lacked large-conductance Ca2+-activated K+ channels and KCNQ4 channels. This together with the persistently increased Ca2+ influx permitted continued action potential generation. We conclude that TH regulates IHC differentiation and is essential for morphological and functional maturation of their ribbon synapses. We suggest that presynaptic dysfunction of IHCs is a mechanism in congenital hypothyroid deafness.