Hair cell population integrity necessary to preserve vestibular function

Abstract

Regeneration of hair cells is a primary target of gene therapy aimed at restoring vestibular and cochlear functions. Indeed, vestibular dysfunction constitutes a major medical concern, as one of its manifestation, dizziness, affects 15-35% of the general population, with a prevalence rate of 85% for those over 80 of age. Age-related alterations of both vestibular function and the integrity of vestibular hair cells has been reported in humans. However, direct comparisons between structural pathology and vestibular dysfunctions quantifications are lacking in humans and rather limited in animal models, representing a significant gap in current knowledge. Thus far, therapeutic trials in animal models targeting vestibular loss associated with genetic diseases have yielded varied and partial results, and the functional identity and quantity of hair cells sufficient to restore minimal or normal vestibular function remain undefined. Here, we further develop an innovative methodology to bridge the gap between hair cells integrity and functional vestibular loss in individuals. Gradual vestibular deficits were induced through a dose-dependent ototoxic compound, quantified with canal or utricular-specific vestibulo-ocular reflex tests, and were then correlated in all individuals with the loss of type I and type II hair cells in different regions of ampulla and macula. Our findings reveal that the structure-function relationship is nonlinear, with lower bound of approximately 50% of hair cells necessary to retain minimal vestibular function, and threshold exceeding 80% to preserve normal function, thus shedding light on population-coding mechanisms for vestibular response. Our data further support the decisive role of type I, rather than type II, HC in the tested VOR functions.