Pathophysiology and Therapy of Vestibular Disorder
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- Dr Christian CHABBERT (PhD, CR CNRS, HDR, team leader)
- Dr Brahim TIGHILET (PhD, MCU, HDR)
- David PERICAT (AI CNRS)
- Pr Jean-Pierre LAVIEILLE (MD, PUPH, APHM, HDR) associate member
- Dr Marion MONTAVA (MD, PUPH, APHM) associate member
- Audrey BOURDET (AI, SATT Sud-Est, 02/2018-01/2019)
- Pierrick BORDIGA (PhD candidate 09/2015-08/2018)
- Guillaume RASTOLDO (PhD candidate 01/2016-12/2018)
- Emna MAROUANE (PhD candidate 01/2018-12/2020)
- Frédéric XAVIER (PhD candidate 12/2017-11/2020)
Vestibular pathologies are characterized by unpredictable episodes of vertigo, accompanied by postural imbalance, and loss of gaze fixation during movement. They are often also accompanied by dizziness and nausea. These pathologies can be highly disabling, notably because, when they are recurrent, they may lead to psychological and social isolation. In France and the USA, vestibular pathologies represent the third most numerous reason for consulting a physician and 5% of hospital emergencies. Due to their high prevalence, vestibular disorders constitute a significant burden on our health care system. Therapeutic solutions for these pathologies lack specificity and efficacy. This is due to both the lack of knowledge of the pathophysiological mechanisms underlying the different vestibular disorders and the lack of biomarkers to discriminate vestibular impairments and properly direct therapeutic approaches. Our multidisciplinary research team including scientists, faculty teachers, engineers, and clinicians and constitutes a unique and leading structure for the study of the basic mechanisms of vestibular function, thereby meeting a pressing medical need in the field of otoneurology, notably by means of a bench-to-bedside approach.
Scientific Guidelines and Strategy
Over the 2018-2022 period, benefiting from its unique position at the interface between scientific research, clinical research, and industrial transfer, the team aims to:
- Establish a technology platform unique in Europe combining studies on animal models and patients
- Decipher the basic mechanisms underlying vestibular disorders and functional restoration
- Promote outstanding research resulting in high-level scientific production
- Develop better-targeted and more efficient therapeutic tools against vestibular disorders
- Become a key player in clinical transfer in order to have a greater impact on the management of balance disorders
- Promote education on the balance function and vestibular disorders
- Promote the visibility of research in otoneurology and foster the appeal of this scientific area in order to encourage the recruitment of the best researchers and students, and to obtain academic and private sector funding
Team-Work and Collaborative Environment
Our team works in a highly collaborative experimental environment, associating in vitro and in vivo techniques including original study models and methods, and advanced technologies already mastered by the team members and available on the website of the Fédération 3C, with the University hospital ENT department of the Assistance Publique des Hôpitaux de Marseille (APHM) at the Hôpital de la Conception (team specialized in medical otology and surgery and hearing and balance experimental setups). The team’s working strategy is based on the development and full exploration of animal models of vestibular disorders. The search for the pathogenic and neurophysiological supports of the observed symptoms is carried down to cellular and molecular levels. The team benefits from a strong interaction between scientists and clinicians at different levels of the work chain, from the phase of experimental design, up to potential clinical and industrial transfer. Collaboration with clinicians from the ENT service of the Hôpital de la Conception offers the opportunity, in accordance with good practice in clinical research, to check the validity of new diagnostic tests or evaluation of the different pathologies and different clinical situations in dizziness, to test the benefits on vestibular disorders of the development of medical devices, and to assess the therapeutic action of new antivertigo drugs.
Main Research Topics
Over the 2018-2022 period, the team will concentrate its research activity on three main topics: (I) the study of the mechanisms of generation and transmission of vestibular sensory information, and the consequences of their deregulation in the generation of vestibular disorders; (II) the study of the reactive mechanisms evoked upon a vestibular insult and of their involvement into the functional restoration following a peripheral insult, and (III) the optimization of the investigation methods to better diagnose vertigo syndromes.
Our team is founder and member of the GDR Vertige (http://gdrvertige.com)
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I-Generation, Encoding, and Transmission of Vestibular Information: Function and Dysfunctions
Endolymph ionic homeostasis: control, deregulation, and vestibular disorders
The endolymph holds a special place in vestibular physiology and pathophysiology. Without an equivalent in the rest of the body, this liquid, which is highly regulated, constitutes the electrochemical motor of the mechano-electrical transduction process. Many questions remain about the molecular effectors that control the endolymph ionic homeostasis and the consequences of their deregulation in the generation of endolymphatic hydrops and vestibular disorders (Maltret et al. 2014). We are currently addressing these questions by means of an original organotypic culture model of rodent utricle previously developed by our group (Bartolami et al. 2011).
Study of the endolymph using the utricular cyst model. The utricular cyst is a unique experimental model developed by our research group. It allows studying the mechanisms of endolymph homeostasis and hydrostatic pressure control. Adapted from Bartolami et al. J Neurosci (2011).
Maltret A, Wiener-Vacher S, Denis C, Extramiana F, Morisseau-Durand MP, Fressart V, Bonnet D, Chabbert C. Type 2 Short QT syndrome and vestibular dysfunction: mirror of the Jervell and Lange-Nielsen syndrome? International Journal of cardiology (2014) 171(2): 291-3.
Bartolami S, Gaboyard S, Quentin J, Travo C, Cavalier M, Barhanin J, Chabbert C. Critical roles of transitional cells and Na/K-ATPase in the formation of vestibular endolymph. Journal of Neuroscience (2011) Nov 16; 31 (46): 16541-9.
Vestibular neurotransmission: Mechanism, dysfunctions and vestibular disorders
Over the past two decades, our team developed several models and methods to study the mechanisms of neurotransmission at vestibular primary synapses. Special attention was given to deciphering the function of the vestibular calyx synapse, a unique synapse expressed exclusively in the inner ear of the higher vertebrates. We thereby became pioneers in the demonstration of the functional involvement of glutamate receptors in the calyx synapse neurotransmission (Bonsacquet et al. 2006), and were the first to show the original mode of glutamate clearance in the calyx cleft (Dalet et al. 2012). Over the 2018-2022 period, we intend to further our investigations in order decipher the molecular effectors (especially the different types of glutamate receptors) involved in the neurotransmission at mammal vestibular synapses, together with their redistribution during selective synaptic impairments.
Characterization of calyx synapse neurotransmission. A. Micrograph illustrating the approach of the patch-clamp pipette through the surface of the posterior crista to directly access the calyx terminal for loose patch recording. B. Tow-photon imaging of a calyx terminal loaded with Lucifer Yellow after recording. C. Blocking effect of the indicated compounds on the background electrical activity recorded at calyx terminal (taken from Bonsacquet et al. 2006).
Dalet A, Bonsacquet J, Gaboyard-Niay S, Calin-Jageman I, Chidavaenzi RL, Desmadryl G, Goldberg JM, Lysakowski A, Chabbert C. Glutamate transporters EAAT4 and EAAT5 are expressed in vestibular hair cells and calyx endings. PLosOne (2012) 7(9):e46261.
Bonsacquet J, Brugeaud A, Compan V, Desmadryl G, Chabbert C. AMPA type glutamate receptor mediates neurotransmission at turtle vestibular calyx synapse. The Journal of Physiology London (2006) 576:63-71.
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II-Adaptive Mechanisms Involved in Functional Restoration
Mechanisms of peripheral synaptic repair
Acute cochlear or vestibular deafferentations are believed to underlie a majority of auditory and vestibular syndromes, such as noise-induced hearing loss and sudden hearing loss, or labyrinthitis, vestibular neuritis, and Meniere’s disease. There is currently no targeted pharmacological therapy to efficiently repair the inner ear primary synapses under pathological conditions. However, an endogenous process of synapses post-injury self-repair occurs in the mammal ear (Brugeaud et al. 2007). This process allows, under certain conditions, the restoration of hearing and balance. The threefold aim of the present project is to explore the repair processes in inner ear primary synapses, decipher their different phases, and identify the cellular pathways and effectors involved. This will be done by combining histological analyses of inner ear synapses, molecular investigation of the modulation of the gene expression in sensory epithelia and primary neurones, and monitoring of recovery of vestibular function and hearing upon pharmacological modulation of candidate pathways on mouse models of controlled vestibular disorders (Gaboyard-Niay et al. 2016).
How glutamate is regulated in the calyx cleft. The specific disposition of the vestibular calyx terminal prevents any intervention of the glutamate transporter EAAT1 (Glast; expressed in supporting cells) in the regulation of the glutamate concentration in the giant synaptic cleft. We combined approaches by RT-PCR, hybridization in situ, patch-clamp and immunohistochemistry to demonstrate the presence in the vestibular hair cells and the post synaptic terminals of EAAT4 and EAAT5 two glutamate transporters previously described only in the retina bipolar cells and the cerebelum. Interaction between theses two transporters may support the fine regulation of the glutamate concentration at the calyx synapse and the phasic activity in the calyx bearing fibres. Taken from Dalet et al. (2012) Plos One.
Brugeaud A, Travo C, Dememes D, Lenoir M, Llorens J, Puel JL, Chabbert C. Control of hair cell excitability by vestibular primary sensory neurons. Journal of Neuroscience(2007) 27: 3503-3511.
Gaboyard-Niay S, Travo C, Saleur A, Broussy A, Brugeaud A, Chabbert C. Correlation between afferent rearrangements and behavioral deficits after local excitotoxic insult in the mammal vestibule: an animal model of vertigo symptoms? Disease Models and Mechanisms (2016) 9: 1181-1192.
Mechanisms of central compensation
Following damage to the vestibular end-organs, a spontaneous process, referred to as central compensation, allows substantial restoration of posture and balance in patients (Lacour and Tighilet, 2010). The effectiveness of this process is highly case-dependent and its cellular and molecular mechanisms remain poorly understood. BT was the first to show that disruption of local homeostasis within deafferented vestibular nuclei following vestibular insult promotes reactive neurogenesis in adult mammals (Tighilet et al. 2007) and that this new phenomenon is essential to the process of balance restoration (Dutheil et al. 2009). We also reported that GABA is a major regulator of vestibular compensation, not only by coordinating cellular events – including the different steps of reactive neurogenesis – but also by regulating the speed of recovery of posturo-locomotor functions (Dutheil et al., 2013). We recently demonstrated that BDNF signalling is causally involved in lesion-induced reparative neurogenesis in the vestibular nuclei, and that specific markers of excitability, potassium chloride cotransporter KCC2 and GABAA receptors undergo remarkable fluctuations locally, strongly suggesting that GABA acquires a transient depolarizing action in the VN during the recovery period (Dutheil et al., 2016). This novel and original plasticity mechanism could partly explain how the system returns to electrophysiological homeostasis between the deafferented and intact VN, considered in the literature to be a key parameter of vestibular compensation. Our next steps will be to elucidate how the interplay between these cellular effectors promotes the reorganization of the neuronal pathways and the restoration of the activity in the ipsilateral and contralateral vestibular nuclei. This will be done by combining cellular and pharmacological studies on rat and mouse models of unilateral vestibular neurectomy with electrophysiological investigations on brain stem slices. The expected output is to get a full picture of the mechanisms involved in the central compensation process, with the further aim of developing targeted pharmacological approaches to accelerate balance recovery in human.
Cascade of events underlying modulation of chloride homeostasis in the deafferented vestibular nuclei after unilateral vestibular neurectomy. KCC2 Down regulation increases cytoplasmic chloride providing the base for a depolarizing action of GABA. Interestingly, at the same time point (3 days after UVN), a peak of BrdU-positive cells is observed on the lesioned side of the VN and is correlated with a peak of BDNF expression as well. This suggests that BDNF, released by both neurons and glia, could modulate cell proliferation, survival, and excitability. Taken from Dutheil et al. J Neuroscience (2016).
Dutheil S, Watabe I, Sadlaoud K, Tonetto A, Tighilet B. BDNF signaling promotes vestibular compensation by increasing neurogenesis and remodeling the expression of potassium-chloride cotransporter KCC2 and GABAa receptor in the vestibular nuclei. Journal of Neuroscience (2016) 36(23): 6199-6212.
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III- Optimization of Investigation Methods to Improve Diagnosis of Vestibular Syndromes
Treatments of vestibular disorders lack specificity and effectiveness (Chabbert 2013). This significantly impairs the development of targeted therapies adapted to the different types and stages of vestibular disorders. With the aim of improving the diagnostic of vestibular syndromes, we will initiate a collaborative project involving several members of the GDR Vertige over the 2017-2019 period. A first part of the project will consist in searching for novel investigation parameters of postural and balance impairments and developing automatized quantification paradigms. This will be done in collaboration with BIOSEB, a biotech company specialized in the development of diagnostic tools for rodents. A second part of the project, conducted in collaboration with clinicians and vestibular physiotherapist, will consist in optimizing the classification of the vertigo syndromes in a large population of vertigo patients, with the aim of providing more accurate decisional diagrams to the clinicians and vestibular physiotherapists. Through this combined approach, we intend to provide novel diagnostic tools for vestibular disorders and will thereby significantly improve the management of vertigo patients.
5 major publications by team members
- Tighilet B, Péricat D, Frelat A, Cazals Y, Rastoldo G, Boyer F, Dumas O, Chabbert C. Adjustment of the dynamic weight distribution as a sensitive parameter for diagnosis of postural alteration in a rodent model of vestibular deficit. PLoS One (2017) Nov 7;12 (11):e0187472.
- Dutheil S, Watabe I, Sadlaoud K, Tonetto A, Tighilet B. (2016). BDNF signalling promotes vestibular compensation by increasing neurogenesis and remodelling the expression of potassium: chloride cotransporter KCC2 and GABAa receptor in the vestibular Journal of Neuroscience (2016) 36 (23): 6199-212.
- Dutheil S, Escoffier G, Gharbi A, Watabe I, Tighilet B. GABAA receptor agonist and antagonist alter vestibular compensation and different steps of reactive neurogenesis in deafferented vestibular nuclei of adult cats. Journal of Neuroscience (2013) 25; 33 (39): 15555:66.
- Bartolami S, Gaboyard S, Quentin J, Travo C, Cavalier M, Barhanin J, Chabbert C. Critical roles of transitional cells and Na/K-ATPase in the formation of vestibular endolymph. Journal of Neuroscience (2011) 31 (46): 16541-9.
- Brugeaud A, Travo C, Dememes D, Lenoir M, Llorens J, Puel JL, Chabbert C. Control of hair cell excitability by vestibular primary sensory neurons. Journal of Neuroscience (2007) 27: 3503-3511.
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