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QTL Mapping of Endocochlear Potential Differences between C57BL/6J and BALB/cJ mice

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Abstract

We reported earlier that the endocochlear potential (EP) differs between C57BL/6J (B6) and BALB/cJ (BALB) mice, being lower in BALBs by about 10 mV (Ohlemiller et al. Hear Res 220: 10–26, 2006). This difference corresponds to strain differences with respect to the density of marginal cells in cochlear stria vascularis. After about 1 year of age, BALB mice also tend toward EP reduction that correlates with further marginal cell loss. We therefore suggested that early sub-clinical features of the BALB stria vascularis may predispose these mice to a condition modeling Schuknecht’s strial presbycusis. We further reported (Ohlemiller et al. J Assoc Res Otolaryngol 12: 45–58, 2011) that the acute effects of a 2-h 110 dB SPL noise exposure differ between B6 and BALB mice, such that the EP remains unchanged in B6 mice, but is reduced by 40–50 mV in BALBs. In about 25 % of BALBs, the EP does not completely recover, so that permanent EP reduction may contribute to noise-induced permanent threshold shifts in BALBs. To identify genes and alleles that may promote natural EP variation as well as noise-related EP reduction in BALB mice, we have mapped related quantitative trait loci (QTLs) using 12 recombinant inbred (RI) strains formed from B6 and BALB (CxB1–CxB12). EP and strial marginal cell density were measured in B6 mice, BALB mice, their F1 hybrids, and RI mice without noise exposure, and 1–3 h after broadband noise (4–45 kHz, 110 dB SPL, 2 h). For unexposed mice, the strain distribution patterns for EP and marginal cell density were used to generate preliminary QTL maps for both EP and marginal cell density. Six QTL regions were at least statistically suggestive, including a significant QTL for marginal cell density on chromosome 12 that overlapped a weak QTL for EP variation. This region, termed Maced (Marginal cell density QTL) supports the notion of marginal cell density as a genetically influenced contributor to natural EP variation. Candidate genes for Maced notably include Foxg1, Foxa1, Akap6, Nkx2-1, and Pax9. Noise exposure produced significant EP reductions in two RI strains as well as significant EP increases in two RI strains. QTL mapping of the EP in noise-exposed RI mice yielded four suggestive regions. Two of these overlapped with QTL regions we previously identified for noise-related EP reduction in CBA/J mice (Ohlemiller et al. Hear Res 260: 47–53, 2010) on chromosomes 5 and 18 (Nirep). The present map may narrow the Nirep interval to a ~10-Mb region of proximal Chr. 18 that includes Zeb1, Arhgap12, Mpp7, and Gjd4. This study marks the first exploration of natural gene variants that modulate the EP. Their orthologs may underlie some human hearing loss that originates in the lateral wall.

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Acknowledgments

We thank Drs. R.J. Morell (NIDCD) and A.N. Salt (WUSM Dept. Otolaryngology) for comments on the manuscript. Thanks also to Drs. K.R. Johnson (JAX) and R.W. Williams (U. Tennessee Health Sciences Center) for helpful discussions.

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Authors and Affiliations

  1. Department of Otolaryngology, Central Institute for the Deaf at Washington University School of Medicine, Fay and Carl Simons Center for Hearing and Deafness, Washington University School of Medicine, 660 S. Euclid, St. Louis, MO, 63110, USA

    Kevin K. Ohlemiller & Patricia M. Gagnon

  2. Department of Speech and Hearing Science, Ohio State University, Columbus, OH, USA

    Anna L. Kiener

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  1. Kevin K. Ohlemiller
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  2. Anna L. Kiener
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  3. Patricia M. Gagnon
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Correspondence to Kevin K. Ohlemiller.

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Funding Agencies

Supported by NIH R01 DC03454 and DC08321 (KKO), P30 DC04665 (R. Chole), NIH T35 DC008765 (W.W. Clark), and Washington University Medical School Department of Otolaryngology.

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Ohlemiller, K.K., Kiener, A.L. & Gagnon, P.M. QTL Mapping of Endocochlear Potential Differences between C57BL/6J and BALB/cJ mice. JARO 17, 173–194 (2016). https://doi.org/10.1007/s10162-016-0558-8

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  • DOI: https://doi.org/10.1007/s10162-016-0558-8

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