Department of Otolaryngology-Head and Neck Surgery, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200023, China.
Ear Institute, Shanghai Jiaotong University School of Medicine, Shanghai 200125, China.
J Neurosci. 2024 Sep 18;44(38):e1405232024. doi: 10.1523/JNEUROSCI.1405-23.2024.
Ribbon synapses of inner hair cells (IHCs) are uniquely designed for ultrafast and indefatigable neurotransmission of the sound. The molecular machinery ensuring the efficient, compensatory recycling of the synaptic vesicles (SVs), however, remains elusive. This study showed that hair cell knock-out of murine , whose human homolog is responsible for nonsyndromic sensorineural hearing loss DFNA71, resulted in auditory synaptopathy by impairing synaptic endocytosis and recycling. The mutant mice in the C57BL/6J background of either sex had mild hearing loss with severely diminished wave I amplitude of the auditory brainstem response. Membrane capacitance measurements of the IHCs revealed deficiency in sustained synaptic exocytosis and endocytic membrane retrieval. Consistent with the electrophysiological findings, 3D electron microscopy reconstruction showed reduced reserve pool of SVs and endocytic compartments, while the membrane-proximal and ribbon-associated vesicles remain intact. Our results propose an important role of DMXL2 in hair cell endocytosis and recycling of the SVs.
内毛细胞 (IHC) 的带状突触专为声音的超快速和不知疲倦的神经递质传递而设计。然而，确保突触小泡 (SV) 有效、补偿性回收的分子机制仍然难以捉摸。本研究表明，敲除 基因的毛细胞，其人类同源物负责非综合征性感觉神经性听力损失 DFNA71，通过损害突触内吞和回收导致听觉突触病。在 C57BL/6J 背景下的雄性和雌性突变小鼠均表现出轻度听力损失，听觉脑干反应的 I 波幅度严重降低。IHC 的膜电容测量显示持续的突触胞吐作用和内吞膜回收存在缺陷。与电生理发现一致，3D 电子显微镜重建显示 SV 和内吞隔室的储备池减少，而膜近端和带状相关囊泡保持完整。我们的结果表明 DMXL2 在毛细胞内吞作用和 SV 的内吞循环中起重要作用。
