Abstract
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.
Highlights
Synapses converging onto the soma and the highly branched dendritic tree of motoneurons (Mns) have been divided into five different types: S, T, M, F and C [1,2,3,4]
In the first part of this study, we examined the evolution of C-bouton terminals juxtaposed to Mns throughout the life span of wild type (WT) and SOD1 mice
Pair-wise comparison of data obtained in each age group between WT and SOD1 mice revealed that the density of C-terminals was significantly higher at P21 and P40 in SOD1 mice and significantly lower at P100 compared to WT mice (Fig 2C)
Summary
Synapses converging onto the soma and the highly branched dendritic tree of motoneurons (Mns) have been divided into five different types: S, T, M, F and C [1,2,3,4]. C-terminals or Cboutons are characterized by spherical synaptic vesicles and the presence of postsynaptic subsynaptic cisterns [5]. These synapses are cholinergic [6,7,8] and originate from interneurons. Given the importance of cholinergic neuromodulation in spinal locomotor networks, numerous studies have investigated C-bouton morphology in physiological and pathological conditions [11,12]. These synapses are extremely plastic and exhibit morphological changes after operant conditioning [13] or spinal hemisection [14]. The postsynaptic membrane (PSM) adjacent to C-boutons on Mns has been described as a highly organized structure with interdigitating clusters of type-2 muscarinic receptors (M2), small conductance calciumactivated potassium channels (SK2/3) and Kv2.1 channels [12]
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