HCN channels in the mammalian cochlea: Expression pattern, subcellular location, and age‐dependent changes,Journal of Neuroscience Research

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HCN channels in the mammalian cochlea: Expression pattern, subcellular location, and age‐dependent changes
Journal of Neuroscience Research ( IF 2.9 ) Pub Date : 2020-11-12 , DOI: 10.1002/jnr.24754
Maria Luque ₁ , Anneliese Schrott-Fischer ₁ , Jozsef Dudas ₁ , Elisabeth Pechriggl ₂ , Erich Brenner ₂ , Helge Rask-Andersen ₃ , Wei Liu ₃ , Rudolf Glueckert _{1,

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Affiliation

Neuronal diversity in the cochlea is largely determined by ion channels. Among voltage‐gated channels, hyperpolarization‐activated cyclic nucleotide‐gated (HCN) channels open with hyperpolarization and depolarize the cell until the resting membrane potential. The functions for hearing are not well elucidated and knowledge about localization is controversial. We created a detailed map of subcellular location and co‐expression of all four HCN subunits across different mammalian species including CBA/J, C57Bl/6N, Ly5.1 mice, guinea pigs, cats, and human subjects. We correlated age‐related hearing deterioration in CBA/J and C57Bl/6N with expression levels of HCN1, −2, and −4 in individual auditory neurons from the same cohort. Spatiotemporal expression during murine postnatal development exposed HCN2 and HCN4 involvement in a critical phase of hair cell innervation. The huge diversity of subunit composition, but lack of relevant heteromeric pairing along the perisomatic membrane and axon initial segments, highlighted an active role for auditory neurons. Neuron clusters were found to be the hot spots of HCN1, −2, and −4 immunostaining. HCN channels were also located in afferent and efferent fibers of the sensory epithelium. Age‐related changes on HCN subtype expression were not uniform among mice and could not be directly correlated with audiometric data. The oldest mice groups revealed HCN channel up‐ or downregulation, depending on the mouse strain. The unexpected involvement of HCN channels in outer hair cell function where HCN3 overlaps prestin location emphasized the importance for auditory function. A better understanding may open up new possibilities to tune neuronal responses evoked through electrical stimulation by cochlear implants.

中文翻译：

哺乳动物耳蜗中的 HCN 通道：表达模式、亚细胞位置和年龄依赖性变化

耳蜗中的神经元多样性在很大程度上取决于离子通道。在电压门控通道中，超极化激活的环核苷酸门控（HCN）通道以超极化打开并使细胞去极化直到静息膜电位。听觉的功能没有得到很好的阐明，关于定位的知识是有争议的。我们创建了跨不同哺乳动物物种（包括 CBA/J、C57Bl/6N、Ly5.1 小鼠、豚鼠、猫和人类受试者）的所有四个 HCN 亚基的亚细胞定位和共表达的详细图谱。我们将 CBA/J 和 C57Bl/6N 中与年龄相关的听力下降与来自同一队列的个体听觉神经元中 HCN1、-2 和 -4 的表达水平相关联。小鼠出生后发育过程中的时空表达暴露了 HCN2 和 HCN4 参与毛细胞神经支配的关键阶段。亚基组成的巨大多样性，但缺乏沿周膜和轴突初始段的相关异聚体配对，突出了听觉神经元的积极作用。发现神经元簇是 HCN1、-2 和 -4 免疫染色的热点。HCN 通道也位于感觉上皮的传入和传出纤维中。HCN 亚型表达的年龄相关变化在小鼠中并不统一，并且不能与听力数据直接相关。根据小鼠品系，最古老的小鼠组显示 HCN 通道上调或下调。HCN 通道意外参与外毛细胞功能，其中 HCN3 与 prestin 位置重叠，强调了听觉功能的重要性。更好的理解可能为调节人工耳蜗电刺激引起的神经元反应开辟新的可能性。

更新日期：2020-12-20

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