SOD1 Motoneurons Research Articles

The role of mutated SOD1 gene in synaptic stripping and MHC class I expression following nerve axotomy in ALS murine model.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by motoneuron death. Several cellular pathways have been described to be involved in ALS pathogenesis; however, the involvement of presynaptic stripping and the related MHC class I molecules in mutant SOD1 motoneurons remains to be clarified. To this purpose, we here investigated, for the first time, the motoneurons behavior, di per se and after facial axonal injury, in terms of synaptic stripping and MHC class I expression in wild-type (Wt) mice and in a murine model of ALS, the SOD1(G93A) mice, at the presymptomatic and symptomatic stage of the disease. Concerning Wt animals, we found a reduction in synaptophysin immunoreactivity and an increase of MHC class I molecules in facial motoneurons after axotomy. In uninjured motoneurons of SOD1(G93A) mice, an altered presynaptic framework was evident, and this phenomenon increased during the disease course. The alteration in the presynaptic input is related to excitatory fibers. Moreover, after injury, a further decrease of excitatory input was not associated to an upregulation of MHC class I molecules in motoneuron soma. This study demonstrates, for the first time, that the presence of mutated SOD1 protein affects the MHC class I molecules expression, altering the presynaptic input in motoneurons. Nevertheless, a positive MHC class I immunolabeling was evident in glial cells around facial injured motoneurons, underlying an involvement of these cells in synaptic stripping. This study contributes to better understand the involvement of the mutated SOD1 protein in the vulnerability of motoneurons after damage.

Age-Related Changes in Pre- and Postsynaptic Partners of the Cholinergic C-Boutons in Wild-Type and SOD1G93A Lumbar Motoneurons.

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.

Glycine Receptor Channels in Spinal Motoneurons Are Abnormal in a Transgenic Mouse Model of Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a rapidly evolving and fatal adult-onset neurological disease characterized by progressive degeneration of motoneurons. Our previous study showed that glycinergic innervation of spinal motoneurons is deficient in an ALS mouse model expressing a mutant form of human superoxide dismutase-1 with a Gly93→Ala substitution (G93A-SOD1). In this study, we have examined, using whole-cell patch-clamp recordings, glycine receptor (GlyR)-mediated currents in spinal motoneurons from these transgenic mice. We developed a dissociated spinal cord culture model using embryonic transgenic mice expressing enhanced green fluorescent protein (eGFP) driven by the Hb9 promoter. Motoneurons were identified as Hb9-eGFP-expressing (Hb9-eGFP(+)) neurons with a characteristic morphology. To examine GlyRs in ALS motoneurons, we bred G93A-SOD1 mice to Hb9-eGFP mice and compared glycine-evoked currents in cultured Hb9-eGFP(+) motoneurons prepared from G93A-SOD1 embryos and from their nontransgenic littermates. Glycine-evoked current density was significantly smaller in the G93A-SOD1 motoneurons compared with control. Furthermore, the averaged current densities of spontaneous glycinergic miniature IPSCs (mIPSCs) were significantly smaller in the G93A-SOD1 motoneurons than in control motoneurons. No significant differences in GABA-induced currents and GABAergic mIPSCs were observed between G93A-SOD1 and control motoneurons. Quantitative single-cell reverse transcription-PCR found lower GlyRα1 subunit mRNA expression in G93A-SOD1 motoneurons, indicating that the reduction of GlyR current may result from the downregulation of GlyR mRNA expression in motoneurons. Immunocytochemistry demonstrated a decrease of surface postsynaptic GlyR on G93A-SOD1 motoneurons. Our study suggests that selective alterations in GlyR function contribute to inhibitory insufficiency in motoneurons early in the disease process of ALS.