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

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 noiserelated 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.Electronic supplementary material The online version of this article

Application of Mouse Models to Research in Hearing and Balance

“…The divergence may reflect EP reduction that B6 mice do not exhibit . The EP reduction correlates with marginal cell loss, and a QTL for marginal cell density on chromosome 12 (Maced) was recently reported based on work in BALB (Ohlemiller et al 2016). BALBs appear exquisitely vulnerable to noise, both during the early vulnerable period and later (Ohlemiller et al 2000;Ohlemiller et al 2011a), and show acute or permanent EP reduction by intense noise (Ohlemiller et al 2011c).…”

“…Notably, the mouse analog precedes a demonstrated disproportionate EP reduction in female CBA/CaJ mice (Ohlemiller et al 2010), perhaps through mechanisms that may operate in postmenopausal women (Guimaraes et al 2004;Price et al 2009). Moreover, strial marginal cell pathology constitutes both the primary initial age-associated pathology in human stria (Schuknecht et al 1974) and the pathology most predictive of EP decline in aging mice (Ohlemiller 2009;Ohlemiller et al 2010;Ohlemiller et al 2016). The detail with which mice can be studied has revealed some age-associated pathologies (e.g., root cell loss) (Ohlemiller et al 2010) whose effects on hearing remain unclear, and we do not yet know if humans show the same changes.…”

“…The reciprocal cross ensures that a particular allele is not systematically silenced (thus not tested) in every RI strain of a series. RI strains have been used to map both Mendelian and complex hearing traits in mice (Hitzemann et al 2001;Noben-Trauth et al 2010;Nagtegaal et al 2012;Ohlemiller et al 2016). GeneNetwork (http://www.genenetwork.org/ home.html) is a useful web-based resource for the analysis of mouse RI strains.…”

The endocochlear potential as an indicator of reticular lamina integrity after noise exposure in mice

“…Depending on model and conditions, the EP may temporarily either increase or decrease. Acute EP increases have been attributed to changes in the organ of Corti such as prolonged hair cell depolarization or decreased conductance of transducer channels (Ohlemiller et al, 2016). Acute EP decreases appear attributable to injury to the stria or spiral ligament (Ohlemiller and Gagnon, 2007; Ohlemiller et al, 2011a) or to increased leakiness of the organ of Corti, which may ‘short out’ the EP (Ahmad et al, 2003).…”

“…Thus we suggested that the genes and processes that underlie these strain differences primarily impact cochlear lateral wall. One or more of the underlying genes lies on proximal chromosome 18 ( Nirep QTL) (Ohlemiller et al, 2010, 2016). …”