Preventing Presbycusis in Mice with Enhanced Medial Olivocochlear Feedback

TERREROS, GONZALO; BOERO, L; CASTAGNA, VALERIA C.; SILVA, SEBASTIÁN; MOGLIE, MARCELO J.; MAASS, JUAN C.; FUCHS, PAUL A.; DELANO, PAUL H.; ELGOYHEN, ANA BELÉN; GÓMEZ CASATI, ME

Congreso; 43RD ANNUAL MidWinter Meeting; 2020

?Growing old? is the most common cause of hearingloss. Age-related hearing loss first affects the abilityto understand speech in background noise, even when auditory thresholds in quiet are normal. It hasbeen suggested that cochlear synaptopathy is anearly contributor to age-related auditory decline.We characterized age-related cochlear synapticdegeneration and hair cell loss in mice with enhancedβ9β10 cholinergic nicotinic receptors (β9KI mice)that mediate inhibitory medial olivocochlear (MOC)feedback. Auditory brainstem responses (ABR) wererecorded to evaluate cochlear function at 6 months and1 year of age in WT and β9KI mice. ABR thresholds weresignificantly elevated by 5-20 dB SPL in aged comparedto young WT mice at all frequencies (Friedman test, p0.05). Distortionproduct otoacoustic emissions (DPOAE) responsesin aged WT ears were elevated by 5-30 dB SPL at allthe frequencies (Friedman test, p< 0.01). In contrast,no alteration in DPOAE thresholds was observed in 1year-old β9KI mice (Friedman test, p >0.05), indicatingthat OHC function is not degraded in aged mice withenhanced MOC inhibition. Suprathreshold ABR peak 1amplitudes was not altered in young β9KI compared tothe same age WT mice (Mann-Whitney test, p >0.05).However, at 1 year there was a reduction in amplitudesin WT ears that was significant at high frequencies whencompared to mutant mice (Mann-Whitney test, p< 0.01at 22.65, 32 and 45.25 kHz). IHC-afferent synapseswere identified by immunostaining with antibodiesagainst CtBP2-Ribeye and GluA2 AMPA-type glutamatereceptors. The numbers of colocalized synaptic punctaper IHC were not different in β9KI compared to WT miceat 6 months of age. Notably, at 1 year of age the numberof synaptic markers per IHC were higher in mice withenhanced MOC function at all the cochlear locations(Mann-Whitney test, p< 0.0001), suggesting that thestrength of the olivocochlear reflex restrains cochlearsynaptopathy. Quantification of hair cells showed that inaged WT there was some loss of OHCs compared toβ9KI ears that was significant at the apical and basalcochlear region (Mann-Whitney test, p< 0.01), indicatingthat the enhanced strength of the MOC system providesthe protective effect against OHC damage. Thus,the present study provides the first proof-of-principlesupporting enhancement of the MOC system as a viableapproach for prevention of auditory function declineduring aging.