Vetter Douglas E, Katz Eleonora, Maison Stéphane F, Taranda Julián, Turcan Sevin, Ballestero Jimena, Liberman M Charles, Elgoyhen A Belén, Boulter Jim
Department of Neuroscience, Tufts University School of Medicine, Boston, MA 02111, USA.
Proc Natl Acad Sci U S A. 2007 Dec 18;104(51):20594-9. doi: 10.1073/pnas.0708545105. Epub 2007 Dec 12.
Although homomeric channels assembled from the alpha9 nicotinic acetylcholine receptor (nAChR) subunit are functional in vitro, electrophysiological, anatomical, and molecular data suggest that native cholinergic olivocochlear function is mediated via heteromeric nAChRs composed of both alpha9 and alpha10 subunits. To gain insight into alpha10 subunit function in vivo, we examined olivo cochlear innervation and function in alpha10 null-mutant mice. Electrophysiological recordings from postnatal (P) days P8-9 inner hair cells revealed ACh-gated currents in alpha10(+/+) and alpha10(+/-) mice, with no detectable responses to ACh in alpha10(-/-) mice. In contrast, a proportion of alpha10(-/-) outer hair cells showed small ACh-evoked currents. In alpha10(-/-) mutant mice, olivocochlear fiber stimulation failed to suppress distortion products, suggesting that the residual alpha9 homomeric nAChRs expressed by outer hair cells are unable to transduce efferent signals in vivo. Finally, alpha10(-/-) mice exhibit both an abnormal olivocochlear morphology and innervation to outer hair cells and a highly disorganized efferent innervation to the inner hair cell region. Our results demonstrate that alpha9(-/-) and alpha10(-/-) mice have overlapping but nonidentical phenotypes. Moreover, alpha10 nAChR subunits are required for normal olivocochlear activity because alpha9 homomeric nAChRs do not support maintenance of normal olivocochlear innervation or function in alpha10(-/-) mutant mice.
尽管由α9烟碱型乙酰胆碱受体（nAChR）亚基组装而成的同聚体通道在体外具有功能，但电生理、解剖学和分子数据表明，天然胆碱能橄榄耳蜗功能是通过由α9和α10亚基组成的异聚体nAChR介导的。为了深入了解α10亚基在体内的功能，我们研究了α10基因敲除小鼠的橄榄耳蜗神经支配和功能。对出生后（P）第8 - 9天的内毛细胞进行电生理记录发现，α10（+/ +）和α10（+ / -）小鼠的内毛细胞存在乙酰胆碱门控电流，而α10（- / -）小鼠对乙酰胆碱无可检测到的反应。相比之下，一部分α10（- / -）外毛细胞显示出小的乙酰胆碱诱发电流。在α10（- / -）突变小鼠中，橄榄耳蜗纤维刺激未能抑制畸变产物，这表明外毛细胞表达的残余α9同聚体nAChR在体内无法转导传出信号。最后，α10（- / -）小鼠表现出橄榄耳蜗形态和对外毛细胞的神经支配异常，以及对内毛细胞区域的传出神经支配高度紊乱。我们的结果表明，α9（- / -）和α10（- / -）小鼠具有重叠但不完全相同的表型。此外，α10 nAChR亚基是正常橄榄耳蜗活动所必需的，因为在α10（- / -）突变小鼠中，α9同聚体nAChR不支持维持正常的橄榄耳蜗神经支配或功能。
