The medial olivocochlear system: insights from genetically modified mice

ELGOYHEN AB

Boston

Congreso; 7th Molecular Biology of Hearing and Deafness Meeting; 2009

THE MEDIAL OLIVOCOCHLEAR SYSTEM: INSIGHTS FROM GENETICALLY MODIFIED MICE. Ana Belén Elgoyhen. Institute for Research in Genetic Engineering and Molecular Biology (CONICET), Buenos Aires, Argentina. 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. The medial olivocochlear (MOC) efferents originate in the medial portion of the superior olivary complex and project to outer hair cells (OHCs) of the organ of Corti, where large synaptic contacts are formed. Activation of the MOC pathway, either by sound or by shock trains delivered to the bundle at the floor of the IVth ventricle, reduces cochlear sensitivity through the action of the neurotransmitter acetylcholine on nicotinic receptors (nAChRs) at the base of OHCs. While significant progress has been made in defining the cellular mechanisms of hair cell inhibition, the functional role[s] of this sound-evoked feedback system, including control of the dynamic range of hearing, improvement of signal detection in background noise, mediating selective attention, and protection from acoustic injury, remain controversial. The oligomeric structure of the hair cell nAChR has been defined: a9 and a10 subunits arrange into a pentameric assembly with a likely (a9)2(a10)3 stoichiometry. Current data supports the notion that activation of the a9a10 nAChR leads to an increase in intracellular Ca2+ and the subsequent opening of small conductance Ca2+-activated K+ SK2 channels, thus leading to hyperpolarization of hair cells. Genetically modified mice have played a crucial role in defining the function of this nAChR of hair cells. During my talk I will review the data obtained from these studies. I will first go over results from subunit specific gene knock-out mice that have helped establish that both a9 and a10 subunits are necessary to form the nAChR mediating synaptic transmission between MOC fibers and outer hair cells of the cochlea. I will then discuss recent data whereby making use of a complementary knock-in strategy we have established that a9-containing nAChRs are sufficient to underlie two effects ascribed to the MOC efferent innervation of hair cells: inhibition of cochlear sensitivity and protection from sound-induced permanent acoustic trauma.