Reduction in the motoneuron inhibitory/excitatory synaptic ratio in an early-symptomatic mouse model of amyotrophic lateral sclerosis.
Excitotoxicity is a widely studied mechanism underlying motoneuron degeneration in amyotrophic lateral sclerosis (ALS). Synaptic alterations that produce an imbalance in the ratio of inhibitory/excitatory synapses are expected to promote or protect against motoneuron excitotoxicity. In ALS patients, motoneurons suffer a reduction in their synaptic coverage, as in the transition from the presymptomatic (2-month-old) to early-symptomatic (3-month-old) stage of the hSOD1(G93A) mouse model of familial ALS. Net synapse loss resulted from inhibitory bouton loss and excitatory synapse gain. Furthermore, in 3-month-old transgenic mice, remaining inhibitory but not excitatory boutons attached to motoneurons showed reduction in the active zone length and in the spatial density of synaptic vesicles in the releasable pool near the active zone. Bouton degeneration/loss seems to be mediated by bouton vacuolization and by mechanical displacement due to swelling vacuolated dendrites. In addition, chronic treatment with a nitric oxide (NO) synthase inhibitor avoided inhibitory loss but not excitatory gain. These results indicate that NO mediates inhibitory loss occurring from the pre- to early-symptomatic stage of hSOD1(G93A) mice. This work contributes new insights on ALS pathogenesis, recognizing synaptic re-arrangement onto motoneurons as a mechanism favoring disease progression rather than as a protective homeostatic response against excitotoxic events.
Sunico
Carmen R
CR
Grupo de Neurodegeneración y Neuroreparación, Área de Fisiología, Facultad de Medicina, Universidad de Cádiz, Cádiz, Spain.
Domínguez
Germán
G
García-Verdugo
José Manuel
JM
Osta
Rosario
R
Montero
Fernando
F
Moreno-López
Bernardo
B
D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D008854:Microscopy, Electron; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology*; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D009569:Nitric Oxide / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics*; D000072105:Superoxide Dismutase-1; D013569:Synapses / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D050599:Vesicular Glutamate Transport Protein 2 / Q000378:metabolism; D050495:Vesicular Inhibitory Amino Acid Transport Proteins / Q000378:metabolism
C493477:Slc17a6 protein, mouse; D050599:Vesicular Glutamate Transport Protein 2; D050495:Vesicular Inhibitory Amino Acid Transport Proteins; C492244:Viaat protein, mouse; D009569:Nitric Oxide; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1