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In a previous study, we observed spontaneous restoration of vestibular function in young adult rodents following excitotoxic injury of the neuronal connections within vestibular endorgans. The functional restoration was supported by a repair of synaptic contacts between hair cells and primary vestibular neurons. This process was observed in 2/3 of the animals studied and occurred within 5 days following the synaptic damage. To assess whether repair capacity is a fundamental trait of vestibular endorgans and to decipher the cellular mechanisms supporting such a repair process, we studied the neuronal regeneration and synaptogenesis in co-cultures of vestibular epithelia and Scarpa's ganglion from young and adult rodents. We demonstrate that, under specific culture conditions, primary vestibular neurons from young mice or rats exhibit robust ability to regenerate nervous processes. When co-cultured with vestibular epithelia, primary vestibular neurons were able to establish de novo contacts with hair cells. Under the present paradigm, these contacts displayed morphological features of immature synaptic contacts. Preliminary observations using co-cultures of adult rodents suggest that this reparative capacity remained in older mice although to a lesser extent. Identifying the basic mechanisms underlying the repair process may provide a basis for novel therapeutic strategies to restore mature and functional vestibular synaptic contacts following damage or loss. [ABSTRACT FROM AUTHOR]

The mechanotransduction of vestibular sensory cells depends on the high endolymphatic potassium concentration ([K+]) maintained by a fine balance between K+ secretion and absorption by epithelial cells. Despite the crucial role of endolymph as an electrochemical motor for mechanotransduction, little is known about the processes that govern endolymph formation. To address these, we took advantage of an organotypic rodent model, which regenerates a genuine neonatal vestibular endolymphatic compartment, facilitating the determination of endolymphatic [K+] and transepithelial potential (Vt) during endolymph formation. While mature Vt levels are almost immediately achieved, K+ accumulates to reach a steady [K+] by day 5 in culture. Inhibition of sensory cell K+ efflux enhance [K+]regardless of the blocker used (FM1.43, amikacin, gentamicin, or gadolinium). Targeting K+secretion with bumetanide partially and transiently reduces [K+],while ouabain application and Kcnel deletion almost abolishes it. Immunofluorescence studies demonstrate that dark cells do not express Na-K-2Cl co transporter 1 (the target of bumetanide) in cultured and young mouse utricles, while Na/K-ATPase (the target of ouabain) is found in dark cells and transitional cells. This global analysis of the involvement ofendolymphatic homeostasis actors in the immature organ ( 1) confirms that KCNE1 channels are necessary forK+ secretion, (2) highlights Na/K-ATPase as the keyendolymphatic K+ provider and shows that Na-K-2Cl cotransporter 1 has a limited impact on K+ influx, and (3) demonstrates that transitional cells are involved inK+ secretion in the early endolymphatic compartment. [ABSTRACT FROM AUTHOR]

The mammalian utricular sensory receptors are commonly believed to be non-spiking cells with electrical activity limited to graded membrane potential changes. Here we provide evidence that during the first post-natal week, the sensory hair cells of the rat utricle express a tetrodotoxin (TTX)-sensitive voltage-gated Na[sup+] current that displays most of the biophysical and pharmacological characteristics of neuronal Na[sup+] current. Single-cell RT-PCR reveals that several α-subunit isoforms of the Na[sup+] channels are co-expressed within a single hair cell, with a major expression of Nav1.2 and Nav1.6 subunits. In neonatal hair cells, 30% of the Na[sup+] channels are available for activation at the resting potential. Depolarizing current injections in the range of the transduction currents are able to trigger TTX-sensitive action potentials. We also provide evidence of a TTX-sensitive activity-dependent brain-derived neurotrophic factor (BDNF) release by early post-natal utricle explants. Developmental analysis shows that Na[sup+] currents decrease dramatically from post-natal day 0 (PO) to P8 and become almost undetectable at P21. Concomitantly, depolarizing stimuli fail to induce both action potential and BDNF release at P20. The present findings reveal that vestibular hair cells express neuronal-like TTX-sensitive Na[sup+] channels able to generate Nat-driven action potentials only during the early post-natal period of development. During the same period an activity-dependent BDNF secretion by utricular explants has been demonstrated. This could be an important mechanism involved in vestibular sensory system differentiation and synaptogenesis. [ABSTRACT FROM AUTHOR]

The function of sensory hair cells of the cochlea and vestibular organs depends on an influx of K+ through apical mechanosensitive ion channels and its subsequent removal over their basolateral membrane. The KCNQ4 (Kv7.4) K+ channel, which is mutated in DFNA2 human hearing loss, is expressed in the basal membrane of cochlear outer hair cells where it may mediate K+ efflux. Like the related K+ channel KCNQ5 (Kv7.5), KCNQ4 is also found at calyx terminals ensheathing type I vestibular hair cells where it may be localized pre- or postsynaptically. Making use of Kcnq4-/- mice lacking KCNQ4, as well as Kcnq4dn/dn and Kcnq5dn/dn mice expressing dominant negative channel mutants, we now show unambiguously that in adult mice both channels reside in postsynaptic calyx-forming neurons, but cannot be detected in the innervated hair cells. Accordingly, whole cell currents of vestibular hair cells did not differ between genotypes. Neither Kcnq4-/-, Kcnq5dn/dn nor Kcnq4-/-/Kcnq5dn/dn double mutant mice displayed circling behavior found with severe vestibular impairment. However, a milder form of vestibular dysfunction was apparent from altered vestibulo-ocular reflexes in Kcnq4-/-/Kcnq5dn/dn and Kcnq4-/- mice. The larger impact of KCNQ4 may result from its preferential expression in central zones of maculae and cristae, which are innervated by phasic neurons that are more sensitive than the tonic neurons present predominantly in the surrounding peripheral zones where KCNQ5 is found. The impact of postsynaptic KCNQ4 on vestibular function may be related to K+ removal and modulation of synaptic transmission. [ABSTRACT FROM AUTHOR]

Introduction: Despite significant advancements in understanding the biochemical, anatomical, and functional impacts of vestibular lesions, developing standardized and effective rehabilitation strategies for patients unresponsive to conventional therapies remains a challenge. Chronic vestibular disorders, characterized by permanent or recurrent imbalances and blurred vision or oscillopsia, present significant complexity in non-pharmacological management. The complex interaction between peripheral vestibular damage and its impact on the central nervous system (CNS) raises questions about neuroplasticity and vestibular compensation capacity. Although fundamental research has examined the consequences of lesions on the vestibular system, the effect of a chronic peripheral vestibular error signal (VES) on the CNS remains underexplored. The VES refers to the discrepancy between sensory expectations and perceptions of the vestibular system has been clarified through recent engineering studies. This deeper understanding of VES is crucial not only for vestibular physiology and pathology but also for designing effective measures and methods of vestibular rehabilitation, shedding light on the importance of compensation mechanisms and sensory integration., Methods: This retrospective study, targeting patients with chronic unilateral peripheral vestibulopathy unresponsive to standard treatments, sought to exclude any interference from pre-existing conditions. Participants were evaluated before and after a integrative vestibular exploratory and rehabilitation program through questionnaires, posturographic tests, and videonystagmography., Results: The results indicate significant improvements in postural stability and quality of life, demonstrating positive modulation of the CNS and an improvement of vestibular compensation., Discussion: Successful vestibular rehabilitation likely requires a multifaceted approach that incorporates the latest insights into neuroplasticity and sensory integration, tailored to the specific needs and clinical progression of each patient. Focusing on compensating for the VES and enhancing sensory-perceptual-motor integration, this approach aims not just to tailor interventions but also to reinforce coherence among the vestibular, visual, and neurological systems, thereby improving the quality of life for individuals with chronic vestibular disorders., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Xavier, Chouin, Tighilet, Chabbert and Besnard.)

Most neurotransmitter systems are represented in the central and peripheral vestibular system and are thereby involved both in normal vestibular signal processing and the pathophysiology of vestibular disorders. However, there is a special relationship between the vestibular system and the histaminergic system. The purpose of this review is to document how the histaminergic system interferes with normal and pathological vestibular function. In particular, we will discuss neurobiological mechanisms such as neuroinflammation that involve histamine to modulate and allow restoration of balance function in the situation of a vestibular insult. These adaptive mechanisms represent targets of histaminergic pharmacological compounds capable of restoring vestibular function in pathological situations. The clinical use of drugs targeting the histaminergic system in various vestibular disorders is critically discussed., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The different types of peripheral vestibulopathies (PVs) or peripheral vestibular disorders (PVDs) are essentially diagnosed on the basis of their clinical expression. The heterogeneity of vestibular symptoms makes it difficult to stratify patients for therapeutic management. Animal models of PVs are a good mean to search for clinical evaluation criteria allowing to objectively analyze the kinetics of expression of the vertigo syndrome and to evaluate the benefits of therapeutic strategies, whether they are pharmacological or rehabilitative. The question of the predictability of these animal models is therefore crucial for the identification of behavioral and biological biomarkers that could then be used in the human clinic. In this review, we propose an overview of the different animal models of PVs, and discuss their relevance for the understanding of the underlying pathophysiological mechanisms and the development of new and more targeted therapeutic approaches., (© 2023 médecine/sciences – Inserm.)

Following partial or total loss of peripheral vestibular inputs, a phenomenon called central vestibular compensation takes place in the hours and days following the injury. This neuroplasticity process involves a mosaic of profound rearrangements within the brain stem vestibular nuclei. Among them, the setting of a new neuronal network is maybe the most original and unexpected, as it involves an adult reactive neurogenesis in a brain area not reported as neurogenic so far. Both the survival and functionality of this newly generated neuronal network will depend on its integration to pre-existing networks in the deafferented structure. Far from being aberrant, this new structural organization allows the use of inputs from other sensory modalities (vision and proprioception) to promote the restoration of the posture and equilibrium. We choose here to detail this model, which does not belong to the traditional niches of adult neurogenesis, but it is the best example so far of the reparative role of the adult neurogenesis. Not only it represents an original neuroplasticity mechanism, interesting for basic neuroscience, but it also opens new medical perspectives for the development of therapeutic approaches to alleviate vestibular disorders., (© 2020 médecine/sciences – Inserm.)

Acute vestibular syndrome (AVS) is characterized by severe posturo-locomotor and vestibulo-oculomotor impairment and accompanies several types of peripheral vestibulopathies (PVP). We know very little about its etiology, how its various symptoms are expressed and how it evolves with age. Robust repair capabilities of primary vestibular synapses have recently been shown to restore behavioral functionality. In this study, we used a mouse model of an excitotoxically induced unilateral vestibular lesion to compare the ability to restore balance and posture between old and young adult mice. We compared the temporal evolution of the evoked vestibular syndrome using a battery of behavioral tests to follow the evolution of postural-locomotor alterations and equilibrium. For the first time, we show that young adult (3 months) and elderly (22 months) mice are together able to restore normal postural-locomotor function following transient unilateral excitotoxic vestibular insult, though with different time courses. This animal study paves way for future, more detailed studies of how the early postural and locomotor disturbances following a unilateral insult are compensated for by various plasticity mechanisms, and in particular how age influences these mechanisms.