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The central question in auditory neurobiology is how the cochleae of humans and other mammals achieve their remarkable sensitivity, frequency selectivity, and enormous dynamic range. Two competing mechanisms have been proposed: mammalian-specific prestin-based outer hair cell (OHC) electromotility and ubiquitous stereociliary motility. Our studies of prestin knockout mice have provided evidence of prestin’s crucial role in cochlear amplification (Liberman et al., Nature 2002). We have since further demonstrated that: 1) prestin-based OHC electromotility is necessary for cochlear amplification (Dallos et al., Neuron, in press); 2) prestin plays a novel role in frequency tuning of cochlear passive mechanical responses and their conversion to neural excitation (Mellado Lagarde et al., Current Biology 2008); 3) prestin-based OHC electromotility does not appear to adjust the operating point of stereociliary motility (Gao et al., PNAS 2007); and 4) Glut5, a previously hypothesized OHC motor protein, is undetectable in OHCs and does not contribute to cochlear amplification (Wu et al., Brain Research, in press). On the basis of these and other advances, we propose a unified amplificatory mechanism that stipulates stereociliary motility for tuning and electromotility for power (Dallos et al., Neuron, in press). We have recently created and characterized a new hypomorphic prestin knockin mouse for studies of cochlear feedback mechanisms. In addition, we have biochemically and structurally characterized the carboxyl cytoplasmic terminus of prestin (Podgorski et al., in preparation). We have also created a mouse model of a putative human prestin mutation. These studies will provide insight into the function of prestin in cochlear amplification and into the pathophysiology of various hearing disorders that involve defective prestin pathways.
We have created three Cre or inducible CreER mouse lines useful for HC-specific gene manipulation (Li et al., Genesis 2004; Tian et al., Dev Dyn 2004; Chow et al., Dev Dyn 2006). We are currently characterizing another prestin-CreER knockin mouse line specific for adult OHCs. These mice are widely available to the hearing research community.
We have also determined that GluRd1 plays important roles in high-frequency hearing loss (Gao et al., MCB 2007). We have found enhanced efferent effects in mice that overexpress SK2 channels in HCs, but unlike a9 AChR overexpressor mice (Zuo et al., PNAS 1999; Maison et al., J. Neurosci. 2002), these mice lacked noise protection mechanisms (Maison et al., J. Neurophysiol 2007). We have identified 17 novel mouse mutants with hearing abnormalities in an ENU-mutagenesis screen (Habiby Kermany et al., Hearing Res 2006). We have also created and characterized a mouse model of DFNA17- and MYH9-related diseases (Parker et al., Brain Res 2006).