Identification and characterisation of new models for age-related hearing loss

Thesis

Age-related hearing loss (ARHL), or Presbycusis, is the most prevalent sensory impairment observed in the elderly. It is a progressive, symmetrical, age-related sensorineural hearing loss, most pronounced at higher frequencies. ARHL is a multifactorial disease, with contribution from both environmental and genetic factors. To date, little progress has been made in determining the genetic loci involved. The aim of my doctorate studies is to elaborate upon the genetics underlying ARHL through the identification and characterization of ENU-induced mouse models of ARHL.

This approach has identified trombone, a recessive model of ARHL arising from the Harwell Ageing Screen. Recurrent auditory phenotyping at 2, 6, 9 and 12 months of age shows that affected animals display elevated ABR thresholds from 9 months of age, when compared to littermates, and these are further increased at 12 months of age. Genome mapping studies identified a 12.5Mb critical region on chromosome 2 and next generation sequencing identified a T>C mutation in the novel deafness gene Slc4a10, causing a leucine to proline substitution in the encoded protein. Immunohistochemical staining of cochlear sections demonstrates that Slc4a10 is expressed in the type II and V fibrocytes of the spiral ligament of wildtype mice, whereas no labelling is observed in Slc4a10^trmb/trmb mice. In addition, ultrastructural studies show progressive sensory hair cell loss (inner and outer) in the Slc4a10^trmb/trmb mice from >6 months of age. Furthermore, histological assessment of the lateral wall identified strial thinning in the Slc4a10^trmb/trmb mice. Given the expression pattern and morphological changes observed, endocochlear potentials were measured in these mice. This identified that Slc4a10^trmb/trmb mice have a chronically low endocochlear potential compared to their wildtype and heterozygous littermates.

My findings establish the presence of Slc4a10 in the inner ear and suggest an important role for this sodium-coupled bicarbonate transporter in normal auditory function. I hypothesize that trombone is a novel model of strial presbycusis and further functional characterization of this model promises to increase our understanding of the pathobiology associated with age-related hearing loss.

Authors: Jeyarajan, P

• DOI: 10.5287/ora-jbrv5qxx1
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford