Molecular Physiology of Hearing, Hearing Research Center Tübingen, Department of Otolaryngology, University of Tübingen Tübingen, Germany.
Front Mol Neurosci. 2013 Aug 9;6:20. doi: 10.3389/fnmol.2013.00020. eCollection 2013.
Voltage-gated L-type Ca(2+) channels (L-VGCCs) like CaV1.2 are assumed to play a crucial role for controlling release of trophic peptides including brain-derived neurotrophic factor (BDNF). In the inner ear of the adult mouse, besides the well-described L-VGCC CaV1.3, CaV1.2 is also expressed. Due to lethality of constitutive CaV1.2 knock-out mice, the function of this ion channel as well as its putative relationship to BDNF in the auditory system is entirely elusive. We recently described that BDNF plays a differential role for inner hair cell (IHC) vesicles release in normal and traumatized condition. To elucidate a presumptive role of CaV1.2 during this process, two tissue-specific conditional mouse lines were generated. To distinguish the impact of CaV1.2 on the cochlea from that on feedback loops from higher auditory centers CaV1.2 was deleted, in one mouse line, under the Pax2 promoter (CaV1.2(Pax2)) leading to a deletion in the spiral ganglion neurons, dorsal cochlear nucleus, and inferior colliculus. In the second mouse line, the Egr2 promoter was used for deleting CaV1.2 (CaV1.2(Egr2)) in auditory brainstem nuclei. In both mouse lines, normal hearing threshold and equal number of IHC release sites were observed. We found a slight reduction of auditory brainstem response wave I amplitudes in the CaV1.2(Pax2) mice, but not in the CaV1.2(Egr2) mice. After noise exposure, CaV1.2(Pax2) mice had less-pronounced hearing loss that correlated with maintenance of ribbons in IHCs and less reduced activity in auditory nerve fibers, as well as in higher brain centers at supra-threshold sound stimulation. As reduced cochlear BDNF mRNA levels were found in CaV1.2(Pax2) mice, we suggest that a CaV1.2-dependent step may participate in triggering part of the beneficial and deteriorating effects of cochlear BDNF in intact systems and during noise exposure through a pathway that is independent of CaV1.2 function in efferent circuits.
电压门控 L 型钙 (Ca2+) 通道 (L-VGCCs)，如 CaV1.2，被认为在控制包括脑源性神经营养因子 (BDNF) 在内的营养肽释放方面发挥着关键作用。在成年小鼠的内耳中，除了描述明确的 L-VGCC CaV1.3 之外，CaV1.2 也有表达。由于组成型 CaV1.2 敲除小鼠的致死性，该离子通道的功能及其在听觉系统中与 BDNF 的潜在关系完全难以捉摸。我们最近描述了 BDNF 在正常和创伤条件下对内耳毛细胞 (IHC) 小泡释放发挥不同的作用。为了阐明 CaV1.2 在这个过程中的假定作用，我们生成了两种组织特异性条件性小鼠系。为了区分 CaV1.2 在耳蜗中的影响与其对来自更高听觉中枢的反馈回路的影响，在一种小鼠系中，使用 Pax2 启动子 (CaV1.2(Pax2)) 删除 CaV1.2，导致螺旋神经节神经元、背侧耳蜗核和下丘缺失。在第二种小鼠系中，使用 Egr2 启动子删除 CaV1.2 (CaV1.2(Egr2)) 在听觉脑干核团中。在这两种小鼠系中，均观察到正常的听力阈值和相等数量的 IHC 释放位点。我们发现 CaV1.2(Pax2) 小鼠的听觉脑干反应波 I 幅度略有降低，但 CaV1.2(Egr2) 小鼠则没有。在噪声暴露后，CaV1.2(Pax2) 小鼠的听力损失程度较轻，与 IHC 中的丝带保持以及听觉神经纤维和高于阈值声音刺激的更高脑中枢的活性降低有关。由于在 CaV1.2(Pax2) 小鼠中发现了耳蜗 BDNF mRNA 水平降低，我们认为 CaV1.2 依赖性步骤可能参与触发完整系统和噪声暴露过程中耳蜗 BDNF 的部分有益和恶化效应，其途径独立于传出回路中 CaV1.2 的功能。
