The sensory epithelia of organs responsible for hearing (the cochlea) and balance (vestibular labyrinth) share a unique subset of cells that respond to mechanical cues. Designated hair cells, they possess apical mechanoreceptors and specialized basolateral membranes that act in concert to transduce mechanical stimuli into electrical signals. In mammals, they are anatomically and functionally divided into inner (IHC) and outer hair cells (OHC). IHC are the sensory receptors responsible for encoding incoming acoustic stimuli. OHC have been implicated in the mechanical amplification of sound and in the fine-tuning of the basilar membrane. It is believed that basilar membrane vibrations induce receptor potentials in OHC, which, via their electromotile response, change the mechanical properties of the basilar membrane in a frequency-selective manner. Interruption of this effect on basilar membrane tuning due to damage of OHC is probably the most common origin of sensorineural hearing loss in humans.
There have been important developments in understanding hearing physiology over recent years. These have included advances in the computational approaches to cochlear mechanics, in the physiology of the inner ear, in the understanding of the cellular and molecular mechanisms of hearing, and in the molecular genetics of hearing loss. Our main contribution to the auditory field has been the identification and characterization of two novel nicotinic receptor (nAChR) subunits, α9 and α10. The subunits assemble to form the receptor that mediates synaptic transmission between efferent olivocochlear fibers and hair cells of the cochlea, one of the few verified examples of postsynaptic function for a non-muscle nAChR. Acetylcholine (ACh) is the principal neurotransmitter released by medial olivocochlear efferent axons, and existing data suggest a central role for an atypical, nAChR located at the synapse between efferent fibers and vertebrate outer hair cells. Current data support a model in which ACh-gated depolarization is followed by activation of small-conductance, calcium-activated potassium channels (SK2) and subsequent hair cell hyperpolarization.
We have been able to define the molecular structure of the mammalian OHC nAChR and have demonstrated that it is assembled from α9 and α10 nAChR subunits in a 2:3 stoichiometry. Although homomeric α9 receptors are functional, the α10 subunit serves as a structural component leading to heteromeric α9α10 nAChRs with particular desensitization kinetics, current-voltage dependency, and sensitivity to extracellular Ca2+. Moreover, we have demonstrated that recombinant α9α10 nAChR and native mammalian hair cell receptors share similar pharmacological and biophysical properties.
Although the role(s) of the efferent innervation to the cochlea is still a matter of debate, the vast majority of efferent effects described to date can generally be ascribed to efferent synapses on the OHC. The medial olivocochlear system projects to the OHC region and medial olivocochlear terminals synapse directly on OHC. Efferent activation produces hyperpolarization of OHC, controls the mechanical state of the cochlea, and, consequently, reduces the sensitivity and the tuning of the auditory nerve fibers. The cochlear efferent system may be responsible for the improvement of signal detection in noise; it could protect the inner ear from noise damage; it may be activated during behavioral tasks involving attention, resulting in the attenuation of the cochlear response to auditory stimuli when attention must be focused elsewhere. Using gene-targeting approaches, we generated an α9 gene (CHRNA9) knockout mouse model and demonstrated that the α9 subunit is essential for olivocochlear function and probably for the development of normal synaptic contacts to cochlear hair cells. In addition, we have generated or are in the final steps towards generating three mouse models: one that expresses CHRNA10 in a constitutive manner, a CHRNA10 knock-out, and a CHRNA9 knock-in that harbors a gain of function mutation in the second transmembrane domain (TM2) region of the α9 subunit.
The long-term goal of our work is to understand the effect of efferent activity on hair cell physiology, the role of efferent input in the normal synaptic development of the inner ear, and the overall contribution of efferent function to hearing. In addition, it is expected that the results obtained will speak to the potential roles for the efferent cholinergic system in hearing impairment produced by loud sound and ototoxic drugs. We now have a useful arsenal of resources to start tackling these important questions. We believe that our ability specifically to alter genes of interest in mice represents an excellent opportunity to determine the molecular mechanisms underlying inner ear function.
Last updated July 2010