The α10 nicotinic acetylcholine receptor subunit is required for normal synaptic function and integrity of the olivocochlear system

doi:10.1073/pnas.0708545105

The α10 nicotinic acetylcholine receptor subunit is required for normal synaptic function and integrity of the olivocochlear system

*Department of Neuroscience, Tufts University School of Medicine, Boston, MA 02111;
**Department of Biomedical Engineering, Tufts University, Boston, MA 02111;
^‡Instituto de Investigaciones en Ingeniería Genética y Biología Molecular (INGEBI), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires 1428, Argentina;
^§Departamento de Fisiología, Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires 1428, Argentina;
^¶Eaton-Peabody Laboratory, Massachusetts Eye and Ear Infirmary, Boston, MA 02114;
^‖Department of Otology and Laryngology, Harvard Medical School, Boston, MA 02115;
^††Departamento de Farmacología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires 1121, Argentina; and
^‡‡Department of Psychiatry and Biobehavioral Sciences, Hatos Research Center for Neuropharmacology, Brain Research and Molecular Biology Institutes, University of California, Los Angeles, CA 90024

Edited by David Julius, University of California, San Francisco, CA, and approved November 7, 2007 (received for review September 10, 2007)

Abstract

Although homomeric channels assembled from the α9 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 α9 and α10 subunits. To gain insight into α10 subunit function in vivo, we examined olivo cochlear innervation and function in α10 null-mutant mice. Electrophysiological recordings from postnatal (P) days P8–9 inner hair cells revealed ACh-gated currents in α10 ^+/+ and α10 ^+/− mice, with no detectable responses to ACh in α10 ^−/− mice. In contrast, a proportion of α10 ^−/− outer hair cells showed small ACh-evoked currents. In α10 ^−/− mutant mice, olivocochlear fiber stimulation failed to suppress distortion products, suggesting that the residual α9 homomeric nAChRs expressed by outer hair cells are unable to transduce efferent signals in vivo. Finally, α10 ^−/− 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 α9 ^−/− and α10 ^−/− mice have overlapping but nonidentical phenotypes. Moreover, α10 nAChR subunits are required for normal olivocochlear activity because α9 homomeric nAChRs do not support maintenance of normal olivocochlear innervation or function in α10 ^−/− mutant mice.

Footnotes

^†To whom correspondence should be addressed at:
Tufts University School of Medicine, Department of Neuroscience, 136 Harrison Avenue, Boston, MA 02111.
E-mail: douglas.vetter{at}tufts.edu
Author contributions: D.E.V. and E.K. contributed equally to this work; D.E.V., E.K., S.F.M., A.B.E., and J. Boulter designed research; D.E.V., E.K., S.F.M., J.T., S.T., J. Ballestero, and J. Boulter performed research; D.E.V., E.K., S.F.M., J.T., S.T., J. Ballestero, M.C.L., A.B.E., and J. Boulter analyzed data; and D.E.V., E.K., and A.B.E. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0708545105/DC1.