Abstract
Amyotrophic lateral sclerosis is characterized by a progressive degeneration of the corticospinal tract motor neurons. Growing evidence suggests that degeneration may begin at the distal axon proceeding in a dying-back pattern. It seemed therefore of interest to investigate synaptic transmission at the neuromuscular junction (NMJ) in pre- and symptomatic phases of the disease. Endplate potentials (EPPs), miniatures endplate potentials (MEPPs) and giant MEPPs (GMEPPs) were recorded from innervated diaphragm muscle fibers from 4–6 and 12-15 weeks-old SOD1(G93A) mice and non-transgenic aged-matched littermates (WT). In the pre-symptomatic phase, SOD1(G93A) mice exhibited a significant increase in the mean amplitude of EPPs together with an increase in the mean quantal content of EPPs, suggesting that more acetylcholine is being released into the synaptic cleft. SOD1(G93A) mice presented a higher frequency of GMEPPs, suggestive of intracellular Ca2+ deregulation in nerve terminals. The increase in the mean amplitude of MEPPs and the decreased mean rise-time of MEPPs in SOD1(G93A) mice point to post-synaptic related changes. In the symptomatic phase, electrophysiological data showed evidence for two NMJ groups in SOD1(G93A) mice: SOD1a and SOD1b. SOD1a group presented reduced mean amplitude of both EPPs and MEPPs. The mean rise-time of MEPPs was increased, when compared to WT and to SOD1b group, indicating impairments in the neuromuscular transmission. In contrast, the neuromuscular transmission of SOD1b group was not different from age-matched WT nor pre-symptomatic SOD1(G93A) mice, being somehow in between both groups. Altogether these results show that the neuromuscular transmission of SOD1(G93A) mice is enhanced in the pre-symptomatic phase. In the symptomatic phase our results are consistent with the hypothesis that the diaphragm of SOD1(G93A) mice is undergoing cycles of denervation/re-innervation supported by mixed neuromuscular junction populations. These early changes in the neuromuscular transmission of SOD1(G93A) mice suggest that the ALS associated events start long before symptoms onset.
Highlights
Amyotrophic Lateral Sclerosis (ALS) is the most common adult-onset motor neuron disease characterized by the degeneration of motor neurons in the corticospinal tract
The results reported show that the mice-diaphragm neuromuscular junction from SOD1(G93A) mice undergoes functional changes early before the symptomatic phase, which do not evolve in the same direction after appearance of motor symptoms
Pre-symptomatic SOD1(G93A) mice presented an enhanced mean amplitude and quantal content of endplate potentials (EPPs) when compared with young controls, suggesting that more acetylcholine is being released to the synaptic cleft
Summary
Amyotrophic Lateral Sclerosis (ALS) is the most common adult-onset motor neuron disease characterized by the degeneration of motor neurons in the corticospinal tract. Most cases have no known cause, 10% are inherited with 20% of these familial cases being caused by a mutation in the copper/zinc superoxide dismutase gene (Cu/Zn, SOD1) Both familial and sporadic forms of ALS present similar pathological and clinical features suggesting a common pathogenesis [1,2]. Several studies have been pointing to a dying-back hypothesis, with an initiation at the motor endplate followed by a retrograde degeneration [3,4,5,6] While this hypothesis suggests the second motor neuron as the first structure of the nervous system to be affected by the disease, little is known about ALS related changes at that the neuromuscular junction level. Regarding the presymptomatic phase of the disease, Souayah and colleagues [9] reported that pre-symptomatic SOD1(G93A) mice (6 weeksold) present a reduced probability of successful neuromuscular transmission at high frequencies of stimulation (70 and 90 Hz)
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