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Gender-specific perturbations in modulatory inputs to motoneurons in a mouse model of Amyotrophic Lateral Sclerosis

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Abstract

The fatal neurodegenerative disease amyotrophic lateral sclerosis (ALS) is characterised by loss of motoneurons of the brainstem and spinal cord, and corticospinal neurons of the motor cortex. There is also increasing evidence of involvement of glial cells and interneurons, with non-cell autonomous disease mechanisms now thought to contribute to motoneuron degeneration in ALS. Given the apparent involvement of altered motoneuron excitability in ALS and the recent demonstration that motoneuron excitability is controlled by C-boutons, a specific class of synaptic input recently shown to originate from a small cluster of spinal interneurons, we hypothesised that perturbations in C-bouton inputs to motoneurons may contribute to altered excitability and the eventual degeneration of motoneurons in ALS. To begin to assess this we performed a detailed, developmental study of the anatomy of C-boutons in a mouse model of ALS (G93A SOD1 mutant). We found that C-bouton number is unchanged in ALS mice compared to wildtype littermates at any age. In contrast, we found that the size of C-boutons increases in ALS mice between postnatal day (P)8 and P30, with boutons remaining larger throughout symptomatic stages (P120-P140). Interestingly, we found that C-boutons are only enlarged in male mice. We found no evidence of concomitant changes in clusters of postsynaptic proteins known to align with C-boutons (Kv2.1 K+ channels and m2-type muscarinic receptors). In conclusion, these data support the involvement of pre-symptomatic changes in C-bouton anatomy in ALS pathogenesis and in particular mechanisms underlying the male bias of this disease.
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Original languageEnglish
Pages (from-to)313-323
JournalNeuroscience
Volume226
DOIs
Publication statusPublished - 13 Dec 2012

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