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The Journal of Neuroscience, January 23, 2008, 28(4):953-962; doi:10.1523/JNEUROSCI.3237-07.2008

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Development/Plasticity/Repair
Exercise-Induced Activation of NMDA Receptor Promotes Motor Unit Development and Survival in a Type 2 Spinal Muscular Atrophy Model Mouse

Olivier Biondi,¹ Clément Grondard,¹ Sylvie Lécolle,¹ Séverine Deforges,¹ Claude Pariset,¹ Philippe Lopes,¹ Carmen Cifuentes-Diaz,² Hung Li,³ Bruno della Gaspera,¹ Christophe Chanoine,¹ and Frédéric Charbonnier¹

¹Equipe Biologie du Développement et de la Différenciation Neuromusculaire, Laboratoire de Neurobiologie des Réseaux Sensorimoteurs, Centre Universitaire des Saints-Pères, Université Paris Descartes, Unité Mixte de Recherche 7060, Centre National de la Recherche Scientifique, F-75270 Paris Cedex 06, France, ²INSERM, U839, Institut du Fer à Moulin, 75005 Paris, France, and ³Institute of Molecular Biology, Academia Sinica, Nankang, Taipei 115, Taiwan

Correspondence should be addressed to Frédéric Charbonnier, Equipe Biologie du Développement et de la Différenciation Neuromusculaire, Laboratoire de Neurobiologie des Réseaux Sensorimoteurs, Centre Universitaire des Saints-Pères, Université Paris Descartes, Unité Mixte de Recherche 7060, Centre National de la Recherche Scientifique, 45 rue des Saints-Pères, F-75270 Paris Cedex 06, France. Email: frederic.charbonnier{at}univ-paris5.fr

Spinal muscular atrophy (SMA) is an inborn neuromuscular disorder caused by low levels of survival motor neuron protein, and for which no efficient therapy exists. Here, we show that the slower rate of postnatal motor-unit maturation observed in type 2 SMA-like mice is correlated with the motor neuron death. Physical exercise delays motor neuron death and leads to an increase in the postnatal maturation rate of the motor-units. Furthermore, exercise is capable of specifically enhancing the expression of the gene encoding the major activating subunit of the NMDA receptor in motor neurons, namely the NR2A subunit, which is dramatically downregulated in the spinal cord of type 2 SMA-like mice. Accordingly, inhibiting NMDA-receptor activity abolishes the exercise-induced effects on muscle development, motor neuron protection and life span gain. Thus, restoring NMDA-receptor function could be a promising therapeutic approach to SMA treatment.

Key words: spinal muscular atrophy; NMDA receptor; neuroprotection; motor-unit development; exercise; MK-801

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Received July 17, 2007; revised Oct. 19, 2007; accepted Nov. 19, 2007.

Correspondence should be addressed to Frédéric Charbonnier, Equipe Biologie du Développement et de la Différenciation Neuromusculaire, Laboratoire de Neurobiologie des Réseaux Sensorimoteurs, Centre Universitaire des Saints-Pères, Université Paris Descartes, Unité Mixte de Recherche 7060, Centre National de la Recherche Scientifique, 45 rue des Saints-Pères, F-75270 Paris Cedex 06, France. Email: frederic.charbonnier{at}univ-paris5.fr

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