Carrott Leanne, Bowl Michael R, Aguilar Carlos, Johnson Stuart L, Chessum Lauren, West Melissa, Morse Susan, Dorning Joanne, Smart Elizabeth, Hardisty-Hughes Rachel, Ball Greg, Parker Andrew, Barnard Alun R, MacLaren Robert E, Wells Sara, Marcotti Walter, Brown Steve D M
Mammalian Genetics Unit, Medical Research Council Harwell, Harwell Campus, Oxfordshire OX11 0RD, United Kingdom.
Mammalian Genetics Unit, Medical Research Council Harwell, Harwell Campus, Oxfordshire OX11 0RD, United Kingdom,
J Neurosci. 2016 Jan 6;36(1):222-34. doi: 10.1523/JNEUROSCI.1808-15.2016.
The Neuroplastin gene encodes two synapse-enriched protein isoforms, Np55 and Np65, which are transmembrane glycoproteins that regulate several cellular processes, including the genesis, maintenance, and plasticity of synapses. We found that an absence of Np65 causes early-onset sensorineural hearing loss and prevented the normal synaptogenesis in inner hair cells (IHCs) in the newly identified mouse mutant pitch. In wild-type mice, Np65 is strongly upregulated in the cochlea from around postnatal day 12 (P12), which corresponds to the onset of hearing. Np65 was specifically localized at the presynaptic region of IHCs. We found that the colocalization of presynaptic IHC ribbons and postsynaptic afferent terminals is greatly reduced in pitch mutants. Moreover, IHC exocytosis is also reduced with mutant mice showing lower rates of vesicle release. Np65 appears to have a nonessential role in vision. We propose that Np65, by regulating IHC synaptogenesis, is critical for auditory function in mammals.
In the mammalian cochlea, the sensory inner hair cells (IHCs) encode auditory information. They do this by converting sound wave-induced mechanical motion of their hair bundles into an electrical current. This current generates a receptor potential that controls release of glutamate neurotransmitter from their ribbon synapses onto the auditory afferent fiber. We show that the synapse-enriched protein Np65, encoded by the Neuroplastin gene, is localized at the IHC presynaptic region. In mutant mice, absence of Np65 causes early-onset sensorineural hearing loss and prevents normal neurotransmitter release in IHCs and colocalization of presynaptic ribbons with postsynaptic afferents. We identified Neuroplastin as a novel deafness gene required for ribbon synapse formation and function, which is critical for sound perception in mammals.
神经塑蛋白基因编码两种富含突触的蛋白异构体，即Np55和Np65，它们是跨膜糖蛋白，可调节多种细胞过程，包括突触的发生、维持和可塑性。我们发现，在新鉴定的小鼠突变体pitch中，Np65的缺失会导致早发性感音神经性听力损失，并阻止内毛细胞（IHC）中正常的突触形成。在野生型小鼠中，从出生后第12天（P12）左右开始，Np65在耳蜗中强烈上调，这与听力开始的时间相对应。Np65特异性定位于IHC的突触前区域。我们发现，在pitch突变体中，突触前IHC带状小体与突触后传入终末的共定位大大减少。此外，突变小鼠的IHC胞吐作用也降低，囊泡释放率较低。Np65似乎在视觉中起非必需作用。我们提出，Np65通过调节IHC突触形成，对哺乳动物的听觉功能至关重要。
在哺乳动物耳蜗中，感觉性内毛细胞（IHC）编码听觉信息。它们通过将声波引起的毛束机械运动转化为电流来实现这一点。这种电流产生一个受体电位，该电位控制谷氨酸神经递质从其带状突触释放到听觉传入纤维上。我们表明，由神经塑蛋白基因编码的富含突触的蛋白Np65定位于IHC突触前区域。在突变小鼠中，Np65的缺失会导致早发性感音神经性听力损失，并阻止IHC中正常的神经递质释放以及突触前带状小体与突触后传入纤维的共定位。我们确定神经塑蛋白是一种新型的致聋基因，是带状突触形成和功能所必需的，对哺乳动物的声音感知至关重要。
