Increase in presynaptic territory of C‐terminals on lumbar motoneurons of G93A SOD1 mice during disease progression

Abstract

Compensatory synaptic plasticity is reported in muscle and the central nervous system of motor neuron disease patients, and transgenic SOD1 mice, but direct ultrastructural evidence for spinal motoneurons is lacking. Prompted by our observation in spinal cords from autopsied patients suggesting selective enlargement of the ultrastructurally distinctive C-type terminal synapsing with spinal motoneurons, we examined the ultrastructural synaptology of lumbar motoneurons during disease progression in age- and sex-matched wild-type mice, transgenic G93A SOD1 mice, and mice overexpressing normal human SOD1 (Wt(SOD1)). Prescribed criteria classified presynaptic terminals of motoneurons into five ultrastructural classes (S, F, T, M, and C). Computerized morphometry on electronmicrographs was used to measure their appositional lengths, coverage of the motoneuron membrane, and sizes of postsynaptic structures. No terminal degeneration occurred in wild-type or Wt(SOD1) mice. In transgenic mice, degeneration of motoneurons and S-terminals and F-terminals commenced presymptomatically (10 weeks), and continued into the symptomatic stage (18 weeks). However, C-terminals were preserved. Morphometry confirmed significant reductions in frequency and membrane coverage for S-terminals and F-terminals between 10 and 18 weeks, but a maintained frequency of C-terminals coupled with increased appositional length and coverage of the motoneuron membrane. Increased C-terminal size was matched by growth of its characterizing postsynaptic cistern and Nissl body. The results reveal selective preservation and increased presynaptic territory of the C-type terminal. As C-terminals derive from cholinergic intrasegmental propriospinal interneurons and may modulate motoneuron excitability, their increased presynaptic territory on surviving motoneurons of transgenic SOD1 mice may represent a means of maintaining excitability, compensating for the loss of overall presynaptic input.

C1q induction and global complement pathway activation do not contribute to ALS toxicity in mutant SOD1 mice

“…5Q). Next, and in line with recent data from SOD1 G93A mutant ALS mice (49,50), C-bouton nerve terminal input (apposed VAChT/Kv2.1 synaptic densities) on surviving large ventral horn motor neurons remained relatively stable during disease in SOD1 G37R mice expressing C1q (Fig. 5 S and T).…”

“…5 S and T). As loss of the corresponding postsynaptic (Kv2.1-positive) density was less pronounced, it is possible that C1q could play a protective role against mutant SOD1 mutant-mediated toxicity in the corresponding cholinergic VO c interneurons, especially as no major loss of C-boutons on motor neurons was reported in ALS mice with normal C1q content (49,50).…”

NO Orchestrates the Loss of Synaptic Boutons from Adult “Sick” Motoneurons: Modeling a Molecular Mechanism

“…In any case, this was concomitant with a decline in cholinergic pre-synaptic terminals around hypoglossal [87] and lumbar [109,125] motoneurons at nearly the end point of disease (>P110). These observations were confirmed by ultrastructural analysis that reported a significant increase (52%) in the frequency of S-type and a reduction (−49%) in F/P-type boutons on transgenic HMNs at P90 [94] and a reduction of both types of boutons on older (P126) lumbar motoneurons [124].…”

“…However, the reduction in the linear density of synir puncta around HMNs [94] was of a higher magnitude (−33% vs. −14%) than that measured in lumbar motoneurons [122] from 3-month-old SOD1 G93A mice. Bouton loss on brainstem and spinal motoneurons was confirmed by ultrastructural analysis [94,124]. Altogether, these findings strongly suggest that reduction in the number and density of boutons can occur before motoneuron loss in this genetic model of fALS.…”

Gender-specific perturbations in modulatory inputs to motoneurons in a mouse model of amyotrophic lateral sclerosis

“…However, when mutant SOD1 is expressed in all motoneurons and oligodendrocytes in chimeras with varying numbers of other cell types expressing mutant SOD1, disease onset appears to be dependent on nonmotor neurons, with the majority of animals exhibiting no disease phenotype (Yamanaka et al, 2008). Support for interneuron involvement in ALS also comes from reports of a general loss of spinal interneurons and alterations in synaptic inputs to motoneurons in human ALS (Matsumoto et al, 1994;Sasaki and Maruyama, 1994;Ince et al, 1995;Stephens et al, 2006) and rodent models (Schutz, 2005;Chang and Martin, 2009;Pullen and Athanasiou, 2009;Sunico et al, 2011). Recent work has revealed loss of a specific class of spinal interneuron, Renshaw cells, in SOD1 mutant mice (Fornai et al, 2008;Chang and Martin, 2009).…”