Ruel Jérôme, Guitton Matthieu J, Gratias Paul, Lenoir Marc, Shen Sanbing, Puel Jean-Luc, Brabet Philippe, Wang Jing
Institute for Neurosciences of Montpellier (INM), University Montpellier, INSERM, Montpellier, France.
Laboratoire de Neurosciences Cognitives, UMR7291 CNRS, Aix-Marseille Université, Marseille, France.
Front Cell Neurosci. 2021 Mar 22;15:658990. doi: 10.3389/fncel.2021.658990. eCollection 2021.
Pituitary adenylyl cyclase-activating polypeptide (PACAP) is a member of the vasoactive intestinal polypeptide (VIP)-the secretin-glucagon family of neuropeptides. They act through two classes of receptors: PACAP type 1 (PAC1) and type 2 (VPAC1 and VPAC2). Among their pleiotropic effects throughout the body, PACAP functions as neuromodulators and neuroprotectors, rescuing neurons from apoptosis, mostly through the PAC1 receptor. To explore the potential protective effect of endogenous PACAP against Noise-induced hearing loss (NIHL), we used a knockout mouse model lacking PAC1 receptor expression (PACR1) and a transgenic humanized mouse model expressing the human PAC1 receptor (TgHPAC1R). Based on complementary approaches combining electrophysiological, histochemical, and molecular biological evaluations, we show PAC1R expression in spiral ganglion neurons and in cochlear apical cells of the organ of Corti. Wild-type (WT), PAC1R, and TgHPAC1R mice exhibit similar auditory thresholds. For most of the frequencies tested after acute noise damage, however, PAC1R mice showed a larger elevation of the auditory threshold than did their WT counterparts. By contrast, in a transgene copy number-dependent fashion, TgHPAC1R mice showed smaller noise-induced elevations of auditory thresholds compared to their WT counterparts. Together, these findings suggest that PACAP could be a candidate for endogenous protection against noise-induced hearing loss.
垂体腺苷酸环化酶激活多肽（PACAP）是血管活性肠肽（VIP）-促胰液素-胰高血糖素神经肽家族的成员。它们通过两类受体发挥作用：PACAP 1型（PAC1）和2型（VPAC1和VPAC2）。在其遍布全身的多效性作用中，PACAP作为神经调节剂和神经保护剂，主要通过PAC1受体拯救神经元免于凋亡。为了探究内源性PACAP对噪声性听力损失（NIHL）的潜在保护作用，我们使用了缺乏PAC1受体表达的基因敲除小鼠模型（PACR1）和表达人PAC1受体的转基因人源化小鼠模型（TgHPAC1R）。基于结合电生理、组织化学和分子生物学评估的互补方法，我们发现PAC1R在螺旋神经节神经元和柯蒂氏器的耳蜗顶端细胞中表达。野生型（WT）、PAC1R和TgHPAC1R小鼠表现出相似的听觉阈值。然而，在急性噪声损伤后测试的大多数频率中，PAC1R小鼠的听觉阈值升高幅度比其野生型对应物更大。相比之下，TgHPAC1R小鼠以转基因拷贝数依赖的方式，与野生型对应物相比，噪声诱导的听觉阈值升高幅度较小。总之，这些发现表明PACAP可能是内源性保护免受噪声性听力损失的候选物质。
