II-Adaptive Mechanisms Involved in Functional Restoration
Mechanisms of peripheral synaptic repair
Acute cochlear or vestibular deafferentations are believed to support a majority of auditory and vestibular syndromes such as noise induced hearing loss and sudden hearing loss, or labyrinthitis, vestibular neuritis and Meniere 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).
Strong post-lesional plasticity at the vestibular primary synapses of the mammal. In order to mimic the deafferentation of the vestibular sensors that take place during peripheral vestibulopathies, we performed excitotoxic deafferentations in the rodent through trans-tympanic administration of glutamate receptor agonists. The analysis of the distances between the pre- and postsynaptic proteins (using immunocytochemistry) allowed to reveal the strong propensity of the primary vestibular synapses to spontaneously reform when the hair cells are preserved. This property could be one of the mechanisms that contribute to the spontaneous restoration of vestibular function observed in human following peripheral vestibulopathies.
Taken from Cassel et al. 2019 DMM
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 endorgans, a spontaneous process referred as central compensation allows substantial restoration of the 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 so far. 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.
Tighilet B, Chabbert C. Adult neurogenesis as a toolbox for balance recovery: Progress in Neurobiology (2019) Mar;174:28-35. doi: 10.1016/j.pneurobio.2019.01.001.