Early functional alterations in membrane properties and neuronal degeneration are hallmarks of progressive hearing loss in NOD mice (original) (raw)

Presbycusis or age-related hearing loss (ARHL) is the most common sensory deficit in the human population. A substantial component of the etiology stems from pathological changes in sensory and non-sensory cells in the cochlea. Using a non-obese diabetic (noD) mouse model, we have characterized changes in both hair cells and spiral ganglion neurons that may be relevant for early signs of age-related hearing loss (ARHL). We demonstrate that hair cell loss is preceded by, or in parallel with altered primary auditory neuron functions, and latent neurite retraction at the hair cell-auditory neuron synapse. The results were observed first in afferent inner hair cell synapse of type I neurites, followed by type ii neuronal cell-body degeneration. Reduced membrane excitability and loss of postsynaptic densities were some of the inaugural events before any outward manifestation of hair bundle disarray and hair cell loss. We have identified profound alterations in type I neuronal membrane properties, including a reduction in membrane input resistance, prolonged action potential latency, and a decrease in membrane excitability. the resting membrane potential of aging type i neurons in the noD, ARHL model, was significantly hyperpolarized, and analyses of the underlying membrane conductance showed a significant increase in K + currents. We propose that attempts to alleviate some forms of ARHL should include early targeted primary latent neural degeneration for effective positive outcomes. Age-related hearing loss (ARHL) is the prevalent form of sensory deficit worldwide. The disease remains less understood, owing to the apparent late-onset phenotype and confounding factors, such as ototoxic drugs, noise trauma, and genetic predispositions 1-3. Although the frequency ranges in which mice (~1-90 kHz) and humans (~0.60-20 kHz) hear are distinct, similarities between the anatomy and physiology of the cochlea make the mouse a compelling animal model to study the mechanisms for ARHL in humans 1,4-6. Previous studies of mutations linked to deafness in mice have provided important insights into human congenital deafness-associated genes 7-10. Additionally, several inbred mouse strains exhibit progressive non-syndromic hearing loss that is expressed phenotypically at advanced ages, which mirrors ARHL in humans 11,12. However, some of the missing mechanistic information for ARHL models is the detailed characterization of early events that occur in the cochlea. Previous studies have described several ARHL mouse models. The ahl locus on chromosome 10 is the hub for the cadherin 23 (Cdh23) gene 12,13 , identified as a major contributor to ARHL in several mouse strains 14. Mutations of two alleles, Cdh23 ahl and ahl2, are responsible for hair cell (HC) loss and an unidentified inner ear pathology, respectively 14-16. These studies have provided a detailed characterization of the pathology of the cochlea in ARHL, but the functional neural mechanisms remain largely unknown. One of the prevailing views is that