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Numerous studies suggest that modulation of the cholinergic system through the use of nicotinic agonists can improve motor function in humans or animals with motor disorders. Specifically, although there are no approved therapeutics for patients with ataxia, the nicotinic receptor agonist varenicline has demonstrated efficacy to improve coordination and gait in several groups of patients with different subtypes of ataxia. Importantly, the mechanism underlying the varenicline’s mechanism of action to improve motor function remains to be elucidated. Thus, the purpose of these experiments was to first quantify gait impairments in rats with olivocerebellar ataxia utilizing an objective treadmill-based system to investigate temporospatial aspects of animals’ gait. These results were used to calculate an index that characterizes deviations from ‘normal’ gait, as similarly employed in clinical studies. The translational validity of this method of gait assessment was investigated by comparing gait impairments between these animals and those reported for humans with ataxia. It was next investigated whether varenicline could attenuate any gait impairments and thus improve motor functioning in these animals, as suggested by clinical findings. Finally, varenicline’s mechanism of action was investigated by attempting to block its effects by pretreating animals with the nicotinic antagonist mecamylamine. Thus, these studies demonstrate the involvement of nicotinic acetylcholine receptors in the mechanism of varenicline’s effects to improve motor functioning. Moreover, these results provide translational methods by which the efficacy of other, more selective nicotinic agonists to improve motor functioning can be tested preclinically prior to their use in humans with ataxia.

La voie olivocérébelleuse (OCP) comprend les fibres grimpantes (CFs), terminaisons axonales des neurones de l'olive inferieure (ION), et leurs cibles, les cellules de Purkinje (PCs). La OCP suit une topographie hautement organisée. A la suite d'une lesion unilatérale de la OCP mature, l'application locale du facteur trophique ‘BDNF’ dans le hemicervelet dénervé induit la reinnervation fonctionnelle des PCs par les CFs. L'objectif de ce travail a était de comprendre les mécanismes activés par le BDNF permettant la plasticité post-lésionnelle dans le OCP mature. Avec un modèle ex vivo chez la souris, nous avons montré que l’injection de BDNF dans le cervelet dénervé augmente la croissance des branchements transverses des CFs intactes. Cette réponse est médiée par l'augmentation de l’expression de Pax3 dans l'ION intact. La surexpression du Pax3 dans l’ION augmente le niveau de PSA-NCAM dans le hemicervelet dénervé, probablement sur les CFs. Cette expression de PSA-NCAM est nécessaire et suffisante pour la réinnervation CF-PC. Nous proposons que la plasticité activée par le BDNF dans l'OCP mature implique le Pax3 et le PSA-NCAM dans l’ION, qui sous-tendent la genèse des branchements des CFs et la reconnaissance correcte des PC dénervés. Pendant le développement de la OCP, la plasticité post-lésionnelle spontanée est plus importante, permettant la compensation anatomique et fonctionnelle. Dans notre modèle ex vivo au stade immature, nous avons montré que cette plasticité spontanée implique l'expression de Pax3 et de PSA-NCAM. Ces résultats suggèrent que la reinnervation post-lésionnelle dans la OCP mature active certains mécanismes de la plasticité développementale. / In the olivocerebellar pathway (OCP) the afferent climbing fibres (CFs), which are the terminal axon projections of the inferior olivary nucleus (ION), innervate cerebellar Purkinje cells (PCs). Following unilateral transection of mature OCP, the addition of the neurotrophic factor BDNF into the denervated cerebellum induces functional CF reinnervation of PCs. What mechanism underlies the BDNF-activated plastic window in the mature OCP and whether recapitulates developmental plasticity remains unknown. Using an optimized ex vivo model of the mouse OCP, we have found that the addition of BDNF into the de-afferented hemicerebellum induces both the outgrowth and elongation of transverse branches from intact CFs. This BDNF-induced plastic response is mediated by the up-regulation of the expression of transcription factor Pax3 in the intact ION. Increased pax3 gene in the ION up-regulates polysialic acid-neural cell adhesion molecule (PSA-NCAM), most likely in the olivocerebellar axons, which was found to be necessary and sufficient for CF reinnervation to PCs. We propose that the BDNF-activated plastic mechanism in the mature OCP involves the afferent Pax3 and PSA-NCAM, which underlies the sprouting of CFs and their appropriate recognition of denervated PCs. Early postnatal OCP shows a spontaneous plasticity following lesion that compensates anatomically and functionally for PC denervation. Using our ex vivo model of the OCP, we found that developmental post-lesion plasticity intrinsically activates and depends on the expression of Pax3 and PSA-NCAM. These results suggest that BDNF treatment in mature OCP reactivates some steps of developmental plasticity mechanisms.

Sensory deprivation in one modality can enhance the development of the remaining modalities via mechanisms of synaptic plasticity. Mice of C3H strain suffers from RD1 retinal degeneration that leads to visual impairment at weaning age. Independently on the retinal degeneration there is also present olivocerebellar degeneration caused by Lurcher mutation. This neurodegenerative disorder causes motor deficits, increased CNS excitability as well as changes in synaptic plasticity. The aim of this study was to evaluate a role of whiskers in compensation of the visual deficit and to assess the influence of the olivocerebellar degeneration on this process. To differentiate contribution of the whiskers from other mechanisms that can take part in the compensation, we investigated the effect of both chronic and acute tactile deprivation. We focused on motor skills (rotarod, beam walking test), gait control (CatWalk system), spontaneous motor activity (open field) and the CNS excitability (audiogenic epilepsy). In the seeing mice without olivocerebellar degeneration, the removal of the whiskers had no effect. In the blind animals without olivocerebellar degeneration, chronic tactile deprivation caused changes in gait and impaired the performance in motor tests. Some other compensatory mechanisms were involved but the...

Sensory deprivation in one modality can enhance the development of the remaining modalities via mechanisms of synaptic plasticity. Mice of C3H strain suffers from RD1 retinal degeneration that leads to visual impairment at weaning age. Independently on the retinal degeneration there is also present olivocerebellar degeneration caused by Lurcher mutation. This neurodegenerative disorder causes motor deficits, increased CNS excitability as well as changes in synaptic plasticity. The aim of this study was to evaluate a role of whiskers in compensation of the visual deficit and to assess the influence of the olivocerebellar degeneration on this process. To differentiate contribution of the whiskers from other mechanisms that can take part in the compensation, we investigated the effect of both chronic and acute tactile deprivation. We focused on motor skills (rotarod, beam walking test), gait control (CatWalk system), spontaneous motor activity (open field) and the CNS excitability (audiogenic epilepsy). In the seeing mice without olivocerebellar degeneration, the removal of the whiskers had no effect. In the blind animals without olivocerebellar degeneration, chronic tactile deprivation caused changes in gait and impaired the performance in motor tests. Some other compensatory mechanisms were involved but the...