title: In vivo NMDA receptor activation accelerates motor unit maturation, protects spinal motor neurons, and enhances SMN2 gene expression in severe spinal muscular atrophy mice.
abstract: Spinal muscular atrophy (SMA), a lethal neurodegenerative disease that occurs in childhood, is caused by the misexpression of the survival of motor neuron (SMN) protein in motor neurons. It is still unclear whether activating motor units in SMA corrects the delay in the postnatal maturation of the motor unit resulting in an enhanced neuroprotection. In the present work, we demonstrate that an adequate NMDA receptor activation in a type 2 SMA mouse model significantly accelerated motor unit postnatal maturation, counteracted apoptosis in the spinal cord, and induced a marked increase of SMN expression resulting from a modification of SMN2 gene transcription pattern. These beneficial effects were dependent on the level of NMDA receptor activation since a treatment with high doses of NMDA led to an acceleration of the motor unit maturation but favored the apoptotic process and decreased SMN expression. In addition, these results suggest that the NMDA-induced acceleration of motor unit postnatal maturation occurred independently of SMN. The NMDA receptor activating treatment strongly extended the life span in two different mouse models of severe SMA. The analysis of the intracellular signaling cascade that lay downstream the activated NMDA receptor revealed an unexpected reactivation of the CaMKII/AKT/CREB (cAMP response element-binding protein) pathway that induced an enhanced SMN expression. Therefore, pharmacological activation of spinal NMDA receptors could constitute a useful strategy for both increasing SMN expression and limiting motor neuron death in SMA spinal cord.
authors.affiliation: Laboratoire de Neurobiologie des Réseaux Sensorimoteurs, Unité Mixte de Recherche 7060, Centre National de la Recherche Scientifique, Université Paris Descartes, Centre Universitaire des Saints-Pères, F-75270 Paris Cedex 06, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Biondi
authors.forename: Julien
authors.initials: J
authors.lastname: Branchu
authors.forename: Gabriel
authors.initials: G
authors.lastname: Sanchez
authors.forename: Camille
authors.initials: C
authors.lastname: Lancelin
authors.forename: Séverine
authors.initials: S
authors.lastname: Deforges
authors.forename: Philippe
authors.initials: P
authors.lastname: Lopes
authors.forename: Claude
authors.initials: C
authors.lastname: Pariset
authors.forename: Sylvie
authors.initials: S
authors.lastname: Lécolle
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Côté
authors.forename: Christophe
authors.initials: C
authors.lastname: Chanoine
authors.forename: Frédéric
authors.initials: F
authors.lastname: Charbonnier
mesh_terms: D000818:Animals; D018920:Coculture Techniques; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000187:drug effects / Q000502:physiology*; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000502:physiology*; D009134:Muscular Atrophy, Spinal / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D016202:N-Methylaspartate / Q000494:pharmacology / Q000627:therapeutic use; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists / Q000378:metabolism*; D012720:Severity of Illness Index; D013116:Spinal Cord / Q000187:drug effects / Q000254:growth & development*; D055540:Survival of Motor Neuron 2 Protein / Q000096:biosynthesis*
chemical_list: D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate; D055540:Survival of Motor Neuron 2 Protein; D016202:N-Methylaspartate