BDNF Signaling Promotes Vestibular Compensation by Increasing Neurogenesis and Remodeling the Expression of Potassium-Chloride Cotransporter KCC2 and GABAA Receptor in the Vestibular Nuclei.
Reactive cell proliferation occurs rapidly in the cat vestibular nuclei (VN) after unilateral vestibular neurectomy (UVN) and has been reported to facilitate the recovery of posturo-locomotor functions. Interestingly, whereas animals experience impairments for several weeks, extraordinary plasticity mechanisms take place in the local microenvironment of the VN: newborn cells survive and acquire different phenotypes, such as microglia, astrocytes, or GABAergic neurons, whereas animals eventually recover completely from their lesion-induced deficits. Because brain-derived neurotrophic factor (BDNF) can modulate vestibular functional recovery and neurogenesis in mammals, in this study, we examined the effect of BDNF chronic intracerebroventricular infusion versus K252a (a Trk receptor antagonist) in our UVN model. Results showed that long-term intracerebroventricular infusion of BDNF accelerated the restoration of vestibular functions and significantly increased UVN-induced neurogenesis, whereas K252a blocked that effect and drastically delayed and prevented the complete restoration of vestibular functions. Further, because the level of excitability in the deafferented VN is correlated with behavioral recovery, we examined the state of neuronal excitability using two specific markers: the cation-chloride cotransporter KCC2 (which determines the hyperpolarizing action of GABA) and GABAA receptors. We report for the first time that, during an early time window after UVN, significant BDNF-dependent remodeling of excitability markers occurs in the brainstem. These data suggest that GABA acquires a transient depolarizing action during recovery from UVN, which potentiates the observed reactive neurogenesis and accelerates vestibular functional recovery. These findings suggest that BDNF and/or KCC2 could represent novel treatment strategies for vestibular pathologies.



In this study, we report for the first time that brain-derived neurotrophic factor potentiates vestibular neurogenesis and significantly accelerates functional recovery after unilateral vestibular injury. We also show that specific markers of excitability, the potassium-chloride cotransporter KCC2 and GABAA receptors, undergo remarkable fluctuations within vestibular nuclei (VN), strongly suggesting that GABA acquires a transient depolarizing action in the VN during the recovery period. This novel plasticity mechanism could explain in part 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. In this context, our results open new perspectives for the development of therapeutic approaches to alleviate the vestibular symptoms and favor vestibular function recovery.
Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06519.
Sophie
S
Dutheil
Laboratoire de Neurosciences Intégratives et Adaptatives, UMR 7260 Aix-Marseille Université-CNRS, Fédération de Recherche 3C, 13331 Marseille Cedex 03, France, and.
Isabelle
I
Watabe
Laboratoire de Neurosciences Intégratives et Adaptatives, UMR 7260 Aix-Marseille Université-CNRS, Fédération de Recherche 3C, 13331 Marseille Cedex 03, France, and.
Karina
K
Sadlaoud
Fédération de Recherche Sciences Chimiques Marseille FR 1739, Pôle PRATIM, 13331 Marseille Cedex 03, France.
Alain
0000-0002-4306-8641
A
Tonetto
Laboratoire de Neurosciences Intégratives et Adaptatives, UMR 7260 Aix-Marseille Université-CNRS, Fédération de Recherche 3C, 13331 Marseille Cedex 03, France, and brahim.tighilet@univ-amu.fr.
Brahim
B
Tighilet
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism* / Q000494:pharmacology; D002227:Carbazoles / Q000494:pharmacology; D002415:Cats; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology; D059329:Cholinergic Neurons / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007839:Functional Laterality; D059330:GABAergic Neurons / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D005968:Glutamate Decarboxylase / Q000378:metabolism; D026121:Indole Alkaloids / Q000494:pharmacology; D008124:Locomotion; D008297:Male; D055495:Neurogenesis / Q000187:drug effects; D009759:Nystagmus, Pathologic / Q000503:physiopathology; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D011187:Posture; D011963:Receptors, GABA-A / Q000235:genetics* / Q000378:metabolism; D020127:Recovery of Function; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D027981:Symporters / Q000235:genetics* / Q000378:metabolism; D014726:Vestibular Nuclei / Q000187:drug effects / Q000293:injuries / Q000378:metabolism*; D000096922:K Cl- Cotransporters
D019208:Brain-Derived Neurotrophic Factor; D002227:Carbazoles; D004791:Enzyme Inhibitors; D005968:Glutamate Decarboxylase; D026121:Indole Alkaloids; D010751:Phosphopyruvate Hydratase; D011963:Receptors, GABA-A; D027981:Symporters; D000096922:K Cl- Cotransporters; C049985:staurosporine aglycone; C402565:glutamate decarboxylase 1
BDNF; GABA; KCC2; gliogenesis; neurogenesis; vestibular compensation