A point mutation in the hair cell nicotinic cholinergic receptor prolongs cochlear inhibition and enhances noise protection.
A point mutation in the hair cell nicotinic cholinergic receptor prolongs cochlear inhibition and enhances noise protection.
复制标题
DOI：
10.1371/journal.pbio.1000018
复制
发表时间：
2009-01-20
期刊：
影响因子：
9.8
通讯作者：
Elgoyhen AB
中科院分区：
文献类型：
--
作者：
Taranda J;Maison SF;Ballestero JA;Katz E;Savino J;Vetter DE;Boulter J;Liberman MC;Fuchs PA;Elgoyhen AB
声音在听觉外周（耳蜗）的传导受到从脑干投射并直接与机械感觉毛细胞突触的传出胆碱能神经元的抑制。听觉神经科学中的一个基本问题是这种反馈在我们的听觉能力中扮演什么角色。在本研究中，我们设计了一种基因修饰的小鼠模型，其中传出胆碱能效应的幅度和持续时间增加，我们评估了这种操作对耳蜗功能的后果。我们在α9烟碱胆碱能亚基第二跨膜结构域的9′位产生了苏氨酸替换亮氨酸（L9′T）的敲入小鼠Chrna 9 L9 ′T系，使含α9受体对乙酰胆碱超敏，脱敏动力学较慢。Chrna 9 L9 ′T等位基因在体外可使传出突触电流延长3倍。在体内，Chrna 9 L9 ′T小鼠耳蜗阈值基线升高，耳蜗反应的传出介导抑制显著增强和延长：士的宁阻断α9α10毛细胞烟碱受体可逆转这两种效应。重要的是，相对于它们的野生型同窝仔，Chrna 9 L9 ′T/L9′T小鼠在暴露于强噪声后表现出较少的永久性听力损失。因此，设计改变α9α10受体门控的点突变提供了一种动物模型，其中不仅传出抑制更强大，而且可以抑制声音诱导的听力损失，表明传出反馈改善声音创伤的能力。烟碱胆碱能受体对高级脑功能是必不可少的。在结构上，这些通过不同同源亚基的无数配体门控五聚体排列起作用。在这里，我们报告的进展，了解在突触的神经元烟碱受体的结构特性。由两个烟碱胆碱能亚单位（α9和α10）组装的受体专门作用于中枢神经系统下行纤维和耳蜗毛细胞之间的突触。这使我们能够显示α9亚基的点突变与α9点突变小鼠耳蜗感觉毛细胞中突触强度的预测改变之间的直接因果关系。此外，这种单一突变导致中枢神经系统对耳蜗的反馈的显著增强。最后，结果是，拥有这种改变的受体的突变小鼠大大提高了对创伤性声音的抵抗力。因此，耳蜗毛细胞上的中枢神经元反馈提供了一个机会来定义烟碱受体在神经系统中可以发挥的一个特定作用，使从生物物理到行为水平的研究成为可能，并促进了预防噪声引起的听力损失的目标。耳蜗毛细胞烟碱胆碱能受体的点突变导致中枢神经系统对耳蜗的反馈增强，并增强对噪声引起的听力损失的保护。
The transduction of sound in the auditory periphery, the cochlea, is inhibited by efferent cholinergic neurons projecting from the brainstem and synapsing directly on mechanosensory hair cells. One fundamental question in auditory neuroscience is what role(s) this feedback plays in our ability to hear. In the present study, we have engineered a genetically modified mouse model in which the magnitude and duration of efferent cholinergic effects are increased, and we assess the consequences of this manipulation on cochlear function. We generated the Chrna9L9′T line of knockin mice with a threonine for leucine change (L9′T) at position 9′ of the second transmembrane domain of the α9 nicotinic cholinergic subunit, rendering α9-containing receptors that were hypersensitive to acetylcholine and had slower desensitization kinetics. The Chrna9L9′T allele produced a 3-fold prolongation of efferent synaptic currents in vitro. In vivo, Chrna9L9′T mice had baseline elevation of cochlear thresholds and efferent-mediated inhibition of cochlear responses was dramatically enhanced and lengthened: both effects were reversed by strychnine blockade of the α9α10 hair cell nicotinic receptor. Importantly, relative to their wild-type littermates, Chrna9L9′T/L9′T mice showed less permanent hearing loss following exposure to intense noise. Thus, a point mutation designed to alter α9α10 receptor gating has provided an animal model in which not only is efferent inhibition more powerful, but also one in which sound-induced hearing loss can be restrained, indicating the ability of efferent feedback to ameliorate sound trauma. Nicotinic cholinergic receptors are essential to higher order brain function. Structurally, these operate through a myriad of ligand-gated pentameric arrangements of different homologous subunits. Here, we report progress in understanding the structural properties of a neuronal nicotinic receptor at the synapse. Receptors assembled from two nicotinic cholinergic subunits (α9 and α10) serve exclusively at the synapse between central nervous system descending fibers and cochlear hair cells. This enabled us to show direct causality between a point mutation of the α9 subunit, and predicted alterations in the synaptic strength in sensory hair cells of the cochlea of α9 point mutant mice. Furthermore, this single mutation results in profound enhancement of central nervous system feedback to the cochlea. And finally, as a consequence, mutant mice possessing this altered receptor have substantially improved resistance to traumatic sound. Thus, central neuronal feedback on cochlear hair cells provides an opportunity to define one specific role that nicotinic receptors can play in the nervous system, enabling study from biophysical to behavioral levels and promoting a target for the prevention of noise-induced hearing loss. A point mutation in the cochlear hair cell nicotinic cholinergic receptor leads to strengthened central nervous system feedback to the cochlea and enhances protection from noise-induced hearing loss.
登录
查看更多内容
影响因子：
2.5
作者：
Maison, Stephane F.;Vetter, Douglas E.;Liberman, M. Charles
通讯作者：
Liberman, M. Charles
影响因子：
4.4
作者：
Lustig, LR;Peng, H;Fuchs, PA
通讯作者：
Fuchs, PA
影响因子：
5.5
作者：
Goutman, JD;Fuchs, PA;Glowatzki, E
通讯作者：
Glowatzki, E
影响因子：
2.5
作者：
KAWASE, T;DELGUTTE, B;LIBERMAN, MC
通讯作者：
LIBERMAN, MC
影响因子：
2.5
作者：
Maison, Stephane F.;Parker, Lisan L.;Liberman, M. Charles
通讯作者：
Liberman, M. Charles