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Développement postnatal d'un modèle murin de sclérose latérale amyotrophique : Acquisitions sensori-motrices, fonctionnement des réseaux lombaires et caractérisation des propriétés électriques et morphologiques des motoneurones.

Abstract : When clinical symptoms of amyotrophic lateral sclerosis (ALS) appear, the majority of spinal motoneurons have already degenerated. Similarly, studies of ALS mouse models have shown that the contractile force of several muscles have diminished by up to 80 percent when clinical symptoms emerge. The etiology of ALS is still unknown and studying the early pathological events could help to improve our understanding of why motoneurons are the principal target of this neurodegenerative disease. Our aim was to identify early abnormalities in transgenic mice expressing a mutated human superoxyde dismutase 1 (SOD1) gene. This SOD1 mutation is found in some ALS patients and these mice are commonly used as a model of this disease. Using behavioral assessments, we showed that the maturation of sensorimotor pathways was disturbed in the SOD1 mice during the first two postnatal weeks. Precisely, the appearance of motor reflexes such as placing, grasping and righting were delayed compared to wild type (WT) animals. These deficits could be explained by the dysfunction of lumbar networks, as hindlimb function was involved in all of the altered motor reflexes. Using brainstem-spinal cord in vitro preparations isolated from pups in the first postnatal week, we showed that SOD1 lumbar networks were barely activated by pharmacological agents. Electrophysiological recordings from these preparations demonstrated that SOD1 lumbar networks were weakly activated by glutamate agonists. However, intracellular recordings of motoneurons showed that the intrinsic properties of SOD1 motoneurons were unchanged compared to WT motoneurons. Thus, these data suggested an imbalance between AMPA and NMDA receptors and a lack of activation of NMDA receptors in SOD1 motoneurons. During the second postnatal week the intrinsic properties of SOD1 lumbar motoneurons were altered. Specifically, SOD1 motoneurons were hypo-excitable and exhibited a lower gain and input resistance compared to motoneurons recorded from WT animals. Concomitantly, we also described a robust increase in the dendritic surface area of SOD1 motoneurons. This surface area increase was sufficient to fully account for the lower input resistance, while the lower gain indicated modifications of ionic conductances. These modifications remain to be characterized. Lastly, with morphometric analysis of 3D reconstructed motoneurons, we showed that dendrites of SOD1 lumbar motoneurons were abnormally over-developed and complex compared with age-matched WT dendrites. SOD1 lumbar motoneurons demonstrated a significant increase in the number of dendritic segments. Importantly, in a pathological context, sacral networks and other spinal neurons that are spared in end-stage ALS did not show such differences. This finding strongly supports the proposition that the postnatal abnormalities described in this work were specific to ALS and also that motoneurons are the principal target of this disease even at early postnatal stages. In conclusion, we showed that motoneuronal dysfunction was evident long before axonal degeneration and the loss of peripheral synapses between motoneurons and muscles (neuromuscular junctions). Moreover, the change in motoneuronal excitability described in this work occurred during a critical period of motor unit maturation and consequently could weaken the neuromuscular junctions.
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https://tel.archives-ouvertes.fr/tel-00537888
Contributor : Julien Amendola <>
Submitted on : Friday, November 19, 2010 - 3:58:26 PM
Last modification on : Friday, October 23, 2020 - 4:45:55 PM
Long-term archiving on: : Sunday, February 20, 2011 - 2:59:31 AM

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Julien Amendola. Développement postnatal d'un modèle murin de sclérose latérale amyotrophique : Acquisitions sensori-motrices, fonctionnement des réseaux lombaires et caractérisation des propriétés électriques et morphologiques des motoneurones.. Neurosciences [q-bio.NC]. Université de la Méditerranée - Aix-Marseille II, 2008. Français. ⟨tel-00537888⟩

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