Neurogenetics Laboratory, Leibniz Institute for Neurobiology, Brenneckestr. 6, 39118, Magdeburg, Germany.
Department Neurochemistry and Molecular Biology, Leibniz Institute for Neurobiology, Brenneckestr. 6, 39118, Magdeburg, Germany.
Brain Struct Funct. 2021 Jun;226(5):1533-1551. doi: 10.1007/s00429-021-02269-w. Epub 2021 Apr 12.
Hearing deficits impact on the communication with the external world and severely compromise perception of the surrounding. Deafness can be caused by particular mutations in the neuroplastin (Nptn) gene, which encodes a transmembrane recognition molecule of the immunoglobulin (Ig) superfamily and plasma membrane Calcium ATPase (PMCA) accessory subunit. This study investigates whether the complete absence of neuroplastin or the loss of neuroplastin in the adult after normal development lead to hearing impairment in mice analyzed by behavioral, electrophysiological, and in vivo imaging measurements. Auditory brainstem recordings from adult neuroplastin-deficient mice (Nptn) show that these mice are deaf. With age, hair cells and spiral ganglion cells degenerate in Nptn mice. Adult Nptn mice fail to behaviorally respond to white noise and show reduced baseline blood flow in the auditory cortex (AC) as revealed by single-photon emission computed tomography (SPECT). In adult Nptn mice, tone-evoked cortical activity was not detectable within the primary auditory field (A1) of the AC, although we observed non-persistent tone-like evoked activities in electrophysiological recordings of some young Nptn mice. Conditional ablation of neuroplastin in Nptn mice reveals that behavioral responses to simple tones or white noise do not require neuroplastin expression by central glutamatergic neurons. Loss of neuroplastin from hair cells in adult Nptn mice after normal development is correlated with increased hearing thresholds and only high prepulse intensities result in effective prepulse inhibition (PPI) of the startle response. Furthermore, we show that neuroplastin is required for the expression of PMCA 2 in outer hair cells. This suggests that altered Ca homeostasis underlies the observed hearing impairments and leads to hair cell degeneration. Our results underline the importance of neuroplastin for the development and the maintenance of the auditory system.
听力缺陷会影响与外界的交流，并严重损害对周围环境的感知。耳聋可能是由于神经纤层蛋白（Nptn）基因的特定突变引起的，该基因编码免疫球蛋白（Ig）超家族和质膜钙 ATP 酶（PMCA）辅助亚基的跨膜识别分子。本研究通过行为、电生理和体内成像测量来研究在正常发育后成年期完全缺乏神经纤层蛋白或神经纤层蛋白缺失是否会导致小鼠听力受损。成年神经纤层蛋白缺陷型（Nptn）小鼠的听觉脑干记录显示，这些小鼠耳聋。随着年龄的增长，Nptn 小鼠的毛细胞和螺旋神经节细胞退化。成年 Nptn 小鼠无法对白噪声做出行为反应，并且单光子发射计算机断层扫描（SPECT）显示其听觉皮层（AC）的基线血流减少。在成年 Nptn 小鼠中，尽管我们在一些年轻的 Nptn 小鼠的电生理记录中观察到非持续的类似音调的诱发电活动，但在 AC 的初级听觉场（A1）中无法检测到音调诱发的皮质活动。在 Nptn 小鼠中条件性敲除神经纤层蛋白表明，对简单音调或白噪声的行为反应不需要中枢谷氨酸能神经元表达神经纤层蛋白。在正常发育后成年 Nptn 小鼠中，毛细胞丧失神经纤层蛋白与听力阈值增加相关，只有高预脉冲强度才能有效抑制惊吓反应的预脉冲抑制（PPI）。此外，我们还表明，神经纤层蛋白是外毛细胞中 PMCA2 表达所必需的。这表明，所观察到的听力损伤是由于钙稳态失衡引起的，并导致毛细胞退化。我们的研究结果强调了神经纤层蛋白对于听觉系统的发育和维持的重要性。
