The organ of Corti, the neuro-sensory epithelium of the cochlea, contains the structures responsible for transducing auditory stimuli to electrical events. These can then be sent to and processed by the central nervous system. Those elements intimately involved with auditory transduction are the hair cells, which in mammals 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. The OHC are under the influence of descending efferent fibers originating in the brain stem. Numerous studies have shown that the major neurotransmitter at the OHC/efferent terminal synapse is acetylcholine. However, cholinergic drugs have been of little benefit to characterize this receptor as either nicotinic or muscarinic. In an effort to characterize the primary structure of the cholinergic receptor present in cochlear hair cells, we have recently cloned a cDNA that encodes a new nicotinic acetylcholine receptor subunit designated alpha9. We have presented evidence which indicates that a receptor composed of the alpha9 subunit is responsible for the signal transduction at the synapse between efferent neuronal terminals and OHC of the cochlea. We have now undertaken a molecular biological and gene targeting approach to further study the properties and function of the alpha9 receptor in the cochlea. Our ultimate goal is to contribute, making use of this methodology, to the study of the physiological role of the cholinergic receptor present on OHC and of the efferent innervation to these cells. In addition, it is expected that the results obtained will be beneficial for the understanding of inner ear pathologies such as hearing impairment produced by acoustic trauma and ototoxic drugs. Our immediate goals to be covered in this application are two-fold. First, we will study the molecular structures that determine the pharmacological properties unique to the alpha9 receptor. Second, we will analyze the gross morphology and synaptogenic events within the cochlea of mice with targeted disruption of the alpha9 gene.
