Age-Related Changes in Pre- and Postsynaptic Partners of the Cholinergic C-Boutons in Wild-Type and SOD1G93A Lumbar Motoneurons.
PLoS ONE. 2015-08-25; 10(8): e0135525
DOI: 10.1371/journal.pone.0135525
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Large cholinergic synaptic terminals known as C-boutons densely innervate the
soma and proximal dendrites of motoneurons that are prone to neurodegeneration in
amyotrophic lateral sclerosis (ALS). Studies using the Cu/Zn-superoxide dismutase
(SOD1) mouse model of ALS have generated conflicting data regarding C-bouton
alterations exhibited during ALS pathogenesis. In the present work, a
longitudinal study combining immunohistochemistry, biochemical approaches and
extra- and intra-cellular electrophysiological recordings revealed that the whole
spinal cholinergic system is modified in the SOD1 mouse model of ALS compared to
wild type (WT) mice as early as the second postnatal week. In WT motoneurons,
both C-bouton terminals and associated M2 postsynaptic receptors presented a
complex age-related dynamic that appeared completely disrupted in SOD1
motoneurons. Indeed, parallel to C-bouton morphological alterations, analysis of
confocal images revealed a clustering process of M2 receptors during WT
motoneuron development and maturation that was absent in SOD1 motoneurons. Our
data demonstrated for the first time that the lamina X cholinergic interneurons,
the neuronal source of C-boutons, are over-abundant in high lumbar segments in
SOD1 mice and are subject to neurodegeneration in the SOD1 animal model. Finally,
we showed that early C-bouton system alterations have no physiological impact on
the cholinergic neuromodulation of newborn motoneurons. Altogether, these data
suggest a complete reconfiguration of the spinal cholinergic system in SOD1
spinal networks that could be part of the compensatory mechanisms established
during spinal development.