Vestibular Deficits in Deafness: Clinical Presentation, Animal Modeling, and Treatment Solutions

Abstract

The inner ear is responsible for both hearing and balance. These functions are dependent on the correct functioning of mechanosensitive hair cells, which convert sound- and motion-induced stimuli into electrical signals conveyed to the brain. During evolution of the inner ear, the major changes occurred in the hearing organ, whereas the structure of the vestibular organs remained constant in all vertebrates over the same period. Vestibular deficits are highly prevalent in humans, due to multiple intersecting causes: genetics, environmental factors, ototoxic drugs, infections and aging. Studies of deafness genes associated with balance deficits and their corresponding animal models have shed light on the development and function of these two sensory systems. Bilateral vestibular deficits often impair individual postural control, gaze stabilization, locomotion and spatial orientation. The resulting dizziness, vertigo, and/or falls (frequent in elderly populations) greatly affect patient quality of life. In the absence of treatment, prosthetic devices, such as vestibular implants, providing information about the direction, amplitude and velocity of body movements, are being developed and have given promising results in animal models and humans. Novel methods and techniques have led to major progress in gene therapies targeting the inner ear (gene supplementation and gene editing), 3D inner ear organoids and reprograming protocols for generating hair cell-like cells. These rapid advances in multiscale approaches covering basic research, clinical diagnostics and therapies are fostering interdisciplinary research to develop personalized treatments for vestibular disorders.

Keywords: animal models; balance disorders; deafness; pathophysiology and gene therapy; rare diseases; vestibulopathy.

Figure 1

Structure and function of the mammalian inner ear, and of the organization of the vestibular and auditory sensory epithelia. (A) The inner ear houses both the hearing and the balance organs, the cochlea and the vestibule, respectively. The membranous labyrinth of the inner ear consists of three semicircular canals, each ending with an ampulla that form the anterior (AC), horizontal (HC), or posterior (PC) crista, two otolith organs (saccule and utricle), and the cochlea. The calyx- and bouton-like afferent innervation of hair cells is presented in green. (B) Cross section of a crista ampullaris, highlighting the organization of the type I and type II hair cells. All the crista hair cells have hair bundles displaying the same polarity orientation, extending into a gelatinous membrane called the cupula. Details of the macular sensory regions' organization are shown in Figure 2. (C) Cross section of the organ of Corti, showing the inner (IHC) and outer (OHCs) hair cells, associated afferent (green) and efferent (dark purple red) neurons and supporting cells.

Figure 2

The vestibular maculae, the hair cells and motion-induced mechano-electrical transduction. (A) Illustration of the morphological and the polarization of hair cells in the utricular and saccular maculae: the black arrows indicate the orientation of the hair bundles. In the utricle, hair cells are oriented with their stereociliary bundles pointing toward the line of polarity reversal (LPR, in red). In the saccule, the stereociliary bundles point away from the LPR. (B–D) Overview of a macular sensory region (B), type I vestibular hair cells (VHCs) (C), and the hair bundle (D). (B) The VHCs extend their hair bundles into the overlying otolithic membrane; an extracellular matrix embedded with otoconia. The kinocilium is colored in cyan. Apart from difference in shape, type I and type II hair cells can also differ according to their innervation. Afferent (green) and efferent (dark purple red) are shown. (B,C) The VHCs are innervated by three types of afferent neurons: The calyx-only class of neurons makes contacts with type I hair cells, essentially in the striola region; dimorphic neurons contact both types of hair cells throughout the sensory epithelium, forming calyces with type I hair cells and boutons with type II hair cells; bouton-only afferents only contact type II hair cells located outside of the central striola region. (D) The basic transduction mechanism is the same in the auditory and vestibular hair cells: a mechanical stimulus bends the stereociliary bundle toward the kinocilium (artificially colored in cyan). The bundle deflection stretches the tip-link, causing an influx of K⁺ and Ca²⁺ ions into the transducing stereocilia. The ensuing change in cell membrane receptor potential leads to glutamate release, generating electrical signals in afferent neurons (green in B,C) forming the VIIIth cranial nerve.

Figure 3

Evolution of the inner ear in vertebrates. The global organization of the five vestibular end organs (utricle, saccule, and the three semicircular canals) has changed very little from fish to current mammals. A sense organ dedicated exclusively to hearing, the papilla, appeared for the first time in amphibians, and then progressively elongates in reptile and birds, and form a spiral in modern mammals.

Figure 4

Functional stratification of genes/proteins causing isolated deafness hearing loss, combined with vestibular deficits. Only human genes responsible for non-syndromic deafness, and for which vestibular deficits have been reported based on clinical findings in affected patients (cf. OMIM numbers); and established role and characterization of corresponding animal models, are shown. These can be grouped into several functional categories: (1) hair bundle development and functioning, (2) synaptic transmission, (3) hair cell's adhesion and maintenance, (4) cochlea ion homeostasis, (5) transmembrane or secreted proteins and extracellular matrix, (6) oxidative stress, metabolism and mitochondrial defects, and (7) transcriptional regulation. DFNAi (red) denotes autosomal-dominant forms of deafness with undefined locus number. The genes/loci in gray denote that they share several functional categories. Similar stratification has been observed for deafness genes (49). Red asterisks indicate those included based on the presence of unambiguous vestibular deficits only in mouse models. More detailed information regarding the deafness causative genes is provided in Supplementary Table S1.