Correlation between afferent rearrangements and behavioral deficits after local excitotoxic insult in the mammalian vestibule: an animal model of vertigo symptoms?

Abstract

Damage to inner ear afferent terminals is believed to result in many auditory and vestibular dysfunctions. The sequence of afferent injuries and repair, as well as their correlation with vertigo symptoms, remains poorly documented. In particular, information on the changes that take place at the primary vestibular endings during the first hours following a selective insult is lacking. In the present study, we combined histological analysis with behavioral assessments of vestibular function in a rat model of unilateral vestibular excitotoxic insult. Excitotoxicity resulted in an immediate but transient alteration of the balance function that was resolved within a week. Concomitantly, vestibular primary afferents underwent a sequence of structural changes followed by spontaneous repair. Within the first two hours after the insult, a first phase of pronounced vestibular dysfunction coincided with extensive swelling of afferent terminals. In the next 24 h, a second phase of significant but incomplete reduction of the vestibular dysfunction was accompanied by a resorption of swollen terminals and fiber retraction. Eventually, within 1 week, a third phase of complete balance restoration occurred. The slow and progressive withdrawal of the balance dysfunction correlated with full reconstitution of nerve terminals. Competitive re-innervation by afferent and efferent terminals that mimicked developmental synaptogenesis resulted in full re-afferentation of the sensory epithelia. By deciphering the sequence of structural alterations that occur in the vestibule during selective excitotoxic impairment, this study offers new understanding of how a vestibular insult develops in the vestibule and how it governs the heterogeneity of vertigo symptoms.

Adjustment of the dynamic weight distribution as a sensitive parameter for diagnosis of postural alteration in a rodent model of vestibular deficit

“…In parallel with the quantitative analysis indicated above, we evaluated qualitatively the vestibular syndrome following UVN using a method recently validated [ 6 ]. The vestibular syndrome evoked in the rat after UVN is composed of typical symptoms previously reported in other vestibular disorder models, such as the cat UVN model [ 8 ], the rodent models of unilateral excitotoxically-induced transient vestibular deafferentation [ 9 , 10 , 11 ] or unilateral chemical labyrintectomy [ 12 ]. These symptoms, which include tumbling, retropulsion, circling, bobbing and head tilt, are together present in the acute phase and sequentially disappear following specific time courses.…”

Selective Optogenetic Stimulation of Glutamatergic, but not GABAergic, Vestibular Nuclei Neurons Induces Immediate and Reversible Postural Imbalance in Mice

“…The researchers set out either, on the basis of an epidemiological rationale, the pathogenic conditions likely to induce vestibular dysfunction and its functional consequences, or the neurophysiological mechanisms likely involved. The first case included: 1) ototoxic-based vestibular damages, reproducing inner ear-specific toxicity of drugs such as aminoglycosides or cisplatin, and food-born ototoxicity (Zhang et al 2003;Hirvonen et al 2005;Xia, Chen, and Yin 2012;Vignaux et al 2012); 2) excitotoxically-induced vestibular damages, reproducing the deleterious consequences on the first synapse of sensory cells suffering (O'Neill et al 1999;Brugeaud et al 2007;Desmadryl et al 2012;Dyhrfjeld-Johnsen et al 2013;Gaboyard-Niay et al 2016); 3) destruction of peripheral receptors through surgical labyrintectomy (Smith and Curthoys 1989;Patk et al 2003;Hitier et al 2010); 4) vestibular neurectomy that relates to the full section of the vestibular nerve. This operation can be achieved either by severing the vestibular nerve peripherally (between the vestibular endorgans and the Scarpa's ganglion) (Li, Godfrey, and Rubin 1995;Hamann et al 1998)or centrally (between the Scarpa's ganglion and the brainstem).…”

Reduced Balance Restoration Capacities Following Unilateral Vestibular Insult in Elderly Mice

“…With the aim to reproduce these excitotoxic damages, we developed in rodents a method of transtympanic administration of glutamate receptors agonists ( 26 ). By combining electron microscopy and immunohistochemical approaches, we confirmed that the local excitotoxic environment generated by the strong afflux of glutamate-receptors agonist evoked selective destruction of the synaptic contacts between vestibular hair cells and primary neurons forming the vestibular nerve ( 26 , 27 ). Swellings and retractions of the postsynaptic terminals were interpreted as the consequence of the massive influx of cations and water through the AMPA-kainate receptors.…”

“…This model allowed us to identify the time course of the different postural-locomotor symptoms that compose AVS. It also highlighted the ability of rodents to quickly restore their balance and posture, based on a robust propensity of peripheral vestibular synapses to spontaneously repair following kainate-induced deafferentation ( 27 ). A recent adaptation of the mouse TTK model and the development of more precise monitoring of both the specific signs of vestibular function and the general behavioral alterations provided the opportunity to better follow the temporal evolution of several specific symptoms of AVS, while better appreciating the different phases that compose this syndrome ( 28 ).…”