scholarly journals Reduced Neuromuscular Quantal Content With Normal Synaptic Release Time Course and Depression in Canine Motor Neuron Disease

2002 ◽  
Vol 88 (6) ◽  
pp. 3305-3314 ◽  
Author(s):  
Mark M. Rich ◽  
Xueyong Wang ◽  
Timothy C. Cope ◽  
Martin J. Pinter
Keyword(s):  
Motor Neuron ◽  
Motor Neuron Disease ◽  
Time Course ◽  
Motor Units ◽  
Medial Gastrocnemius ◽  
Release Time ◽  
Quantal Content ◽  
Deconvolution Analysis ◽  
Quantal Release ◽  
Synaptic Release

Hereditary canine spinal muscular atrophy is an autosomal dominant version of motor neuron disease in which motor units exhibit extensive dysfunction before motor terminal or axonal degeneration appear. We showed in a previous paper that motor endplate currents (EPCs) are reduced and that failures of nerve-evoked EPCs appear in the homozygote medial gastrocnemius (MG) muscle in which failing motor units are also found, suggesting a presynaptic deficit of ACh release. To examine this further, we performed a detailed analysis of synaptic release properties in the MG muscle of homozygotes and compared the results with data from genetically normal control animals. We found that the amplitude of miniature EPCs (mEPC) did not differ between homozygote and normal synapses, indicating that quantal content is reduced at homozygote motor terminals. Consistent with this, deconvolution analysis showed that the maximum release rates at homozygote motor terminals were significantly reduced relative to normal. This analysis also demonstrated that the time course of quantal release at homozygote synapses did not differ from normal. The extent of quantal release depression during high-frequency activation in homozygotes did not differ from normal despite the significant reduction of quantal content and maximum release rate. Surprisingly, the absolute amount of posttetanic potentiation was not decreased at homozygotes motor terminals despite the differences in quantal content. We conclude that failure of homozygote motor unit force during repetitive activity is due to a unique combination of low quantal content and normal release depression and suggest that the primary deficit in homozygote motor terminals is a reduced supply of readily releasable quanta.

scholarly journals Activity-Driven Synaptic and Axonal Degeneration in Canine Motor Neuron Disease

2004 ◽  
Vol 92 (2) ◽  
pp. 1175-1181 ◽  
Author(s):  
Dario I. Carrasco ◽  
Mark M. Rich ◽  
Qingbo Wang ◽  
Timothy C. Cope ◽  
Martin J. Pinter
Keyword(s):  
Motor Neuron ◽  
Motor Neuron Disease ◽  
Motor Unit ◽  
Neuromuscular Junctions ◽  
Muscular Atrophy ◽  
Motor Axon ◽  
Medial Gastrocnemius ◽  
Neuron Activity ◽  
Functional Changes ◽  
Unit Function

The role of neuronal activity in the pathogenesis of neurodegenerative disease is largely unknown. In this study, we examined the effects of increasing motor neuron activity on the pathogenesis of a canine version of inherited motor neuron disease (hereditary canine spinal muscular atrophy). Activity of motor neurons innervating the ankle extensor muscle medial gastrocnemius (MG) was increased by denervating close synergist muscles. In affected animals, 4 wk of synergist denervation accelerated loss of motor-unit function relative to control muscles and decreased motor axon conduction velocities. Slowing of axon conduction was greatest in the most distal portions of motor axons. Morphological analysis of neuromuscular junctions (NMJs) showed that these functional changes were associated with increased loss of intact innervation and with the appearance of significant motor axon and motor terminal sprouting. These effects were not observed in the MG muscles of age-matched, normal animals with synergist denervation for 5 wk. The results indicate that motor neuron action potential activity is a major contributing factor to the loss of motor-unit function and degeneration in inherited canine motor neuron disease.

Properties of self-reinnervated motor units of medial gastrocnemius of cat. II. Axotomized motoneurons and time course of recovery

1986 ◽  
Vol 55 (5) ◽  
pp. 947-965 ◽  
Author(s):  
R. C. Foehring ◽  
G. W. Sypert ◽  
J. B. Munson
Keyword(s):  
Electrical Properties ◽  
Motor Unit ◽  
Fatigue Resistance ◽  
Time Course ◽  
Muscle Fibers ◽  
Motor Units ◽  
Input Resistance ◽  
Medial Gastrocnemius ◽  
Muscle Properties ◽  
Fast Twitch

This study tested the hypothesis that functional connection to muscle is necessary for expression of normal motoneuron electrical properties. Also examined was the time course of self-reinnervation. Properties of individual medial gastrocnemius (MG) motor units were examined following section and reanastomosis of the MG nerve. Stages examined were 3-5 wk (prior to reinnervation, no-re), 5-6 wk (low-re), 9-10 wk (med-re), and 9 mo (long-re, preceding paper) after nerve section. Motor units were classified on the basis of their mechanical response as type fast twitch, fast fatiguing (FF), fast twitch with intermediate fatigue resistance (FI), fast twitch, fatigue resistant (FR), or slow twitch, fatigue resistant (S) (11, 24). Motoneuron electrical properties were measured. Muscle fibers were classified using histochemical methods as type fast glycolytic (FG), fast oxidative glycolytic (FOG), or slow oxidative (SO) (60). Prior to functional reinnervation, MG motoneurons exhibited increased input resistance, decreased rheobase, decreased rheobase/input resistance, and decreased axonal conduction velocity. There was no change in mean afterhyperpolarization (AHP) half-decay time. Normal relationships between motoneuron electrical properties were lost. These data are consistent with dedifferentiation of motoneuron properties following axotomy (35, 47). At 5-6 wk after reanastomosis, motor-unit tensions were small, and motoneuron membrane electrical properties were unchanged from the no-re stage. There were no differences in motoneuron electrical properties between cells that elicited muscle contraction and those that did not. Motor-unit types were first recognizable at the med-re stage. The proportions of fast and slow motor units were similar to normal MG. Within the fast units, there were fewer type-FF units and more type-FI and type-FR units than normal, reflecting a general increase in fatigue resistance at this stage. Neither motoneuron membrane electrical properties nor muscle contractile properties had reached normal values, although both were changed in that direction from the low-re stage. Normal relationships between muscle properties, between motoneuron properties, and between motoneuron and muscle properties were re-established. The correspondence between motor-unit type and motoneuron type was similar to normal or 9 mo reinnervated MG. Muscle-unit tetanic tensions became larger with time after reinnervation. Most of the increase in muscle tension beyond the med-re stage could be accounted for by increase in muscle fiber area. There was an increased proportion of SO muscle fibers observed in the med-re muscles, as at the long-re stage.(ABSTRACT TRUNCATED AT 400 WORDS)

The reorganization of motor units in motor neuron disease

1997 ◽  
Vol 20 (3) ◽  
pp. 306-315 ◽  
Author(s):  
Barbara Emeryk-Szajewska ◽  
Jerzy Kope? ◽  
Anna Karwanska
Keyword(s):  
Motor Neuron ◽  
Motor Neuron Disease ◽  
Motor Units

scholarly journals Reduced Endplate Currents Underlie Motor Unit Dysfunction in Canine Motor Neuron Disease

2002 ◽  
Vol 88 (6) ◽  
pp. 3293-3304 ◽  
Author(s):  
Mark M. Rich ◽  
Robert. F. Waldeck ◽  
Linda C. Cork ◽  
Rita J. Balice-Gordon ◽  
Robert E. W. Fyffe ◽  
...  
Keyword(s):  
Motor Neuron ◽  
Motor Neuron Disease ◽  
Motor Unit ◽  
Conduction Velocity ◽  
Motor Neurons ◽  
Muscle Fiber ◽  
Muscular Atrophy ◽  
Motor Units ◽  
Postnatal Maturation ◽  
Axonal Conduction

Hereditary canine spinal muscular atrophy (HCSMA) is an autosomal dominant degenerative disorder of motor neurons. In homozygous animals, motor units produce decreased force output and fail during repetitive activity. Previous studies suggest that decreased efficacy of neuromuscular transmission underlies these abnormalities. To examine this, we recorded muscle fiber endplate currents (EPCs) and found reduced amplitudes and increased failures during nerve stimulation in homozygotes compared with wild-type controls. Comparison of EPC amplitudes with muscle fiber current thresholds indicate that many EPCs from homozygotes fall below threshold for activating muscle fibers but can be raised above threshold following potentiation. To determine whether axonal abnormalities might play a role in causing motor unit dysfunction, we examined the postnatal maturation of axonal conduction velocity in relation to the appearance of tetanic failure. We also examined intracellularly labeled motor neurons for evidence of axonal neurofilament accumulations, which are found in many instances of motor neuron disease including HCSMA. Despite the appearance of tetanic failure between 90 and 120 days, average motor axon conduction velocity increased with age in homozygotes and achieved adult levels. Normal correlations between motor neuron properties (including conduction velocity) and motor unit properties were also observed. Labeled proximal motor axons of several motor neurons that supplied failing motor units exhibited little or no evidence of axonal swellings. We conclude that decreased release of transmitter from motor terminals underlies motor unit dysfunction in HCSMA and that the mechanisms determining the maturation of axonal conduction velocity and the pattern of correlation between motor neuron and motor unit properties do not contribute to the appearance or evolution of motor unit dysfunction.

Fatigue of single motor units in human masseter

1990 ◽  
Vol 68 (1) ◽  
pp. 26-34 ◽  
Author(s):  
M. A. Nordstrom ◽  
T. S. Miles
Keyword(s):  
Time Course ◽  
Motor Units ◽  
Medial Gastrocnemius ◽  
Type I ◽  
Single Motor Unit ◽  
Single Motor ◽  
Single Motor Units ◽  
Spike Triggered Averaging ◽  
Human Fatigue ◽  
Type I Fibers

The spike-triggered averaging technique was used to determine the time course and extent of fatigue of single motor unit twitches in the human masseter. This is the first report of a fatigue test having been applied to masseter motor units in either animals or humans. The human masseter was found to be comprised predominantly of fast-twitch motor units with a broad spectrum of fatigability. Very few physiological type S units were found, despite histochemical evidence for a substantial population of type I fibers in the masseter. In addition, there was no significant correlation between fatigability and either twitch amplitude or contractile speed in the motor units studied. The latter observations are consistent with the unusual histological features of the masseter. Comparison with other human fatigue data suggests that the extent of fatigue in the present population of masseter motor units after approximately 3,000 activations is similar to that reported for populations of units in first dorsal interosseous and medial gastrocnemius.

scholarly journals Longitudinal multi-modal muscle-based biomarker assessment in motor neuron disease

2019 ◽  
Vol 267 (1) ◽  
pp. 244-256 ◽  
Author(s):  
Thomas M. Jenkins ◽  
James J. P. Alix ◽  
Jacob Fingret ◽  
Taniya Esmail ◽  
Nigel Hoggard ◽  
...  
Keyword(s):  
Motor Neuron ◽  
Motor Neuron Disease ◽  
Tibialis Anterior ◽  
Rating Scale ◽  
Motor Units ◽  
Whole Body ◽  
Major Barrier ◽  
Surrogate Outcome ◽  
Leg Muscles ◽  
Prospective Longitudinal

Abstract Background Clinical phenotypic heterogeneity represents a major barrier to trials in motor neuron disease (MND) and objective surrogate outcome measures are required, especially for slowly progressive patients. We assessed responsiveness of clinical, electrophysiological and radiological muscle-based assessments to detect MND-related progression. Materials and methods A prospective, longitudinal cohort study of 29 MND patients and 22 healthy controls was performed. Clinical measures, electrophysiological motor unit number index/size (MUNIX/MUSIX) and relative T2- and diffusion-weighted whole-body muscle magnetic resonance (MR) were assessed three times over 12 months. Multi-variable regression models assessed between-group differences, clinico-electrophysiological associations, and longitudinal changes. Standardized response means (SRMs) assessed sensitivity to change over 12 months. Results MND patients exhibited 18% higher whole-body mean muscle relative T2-signal than controls (95% CI 7–29%, p < 0.01), maximal in leg muscles (left tibialis anterior 71% (95% CI 33–122%, p < 0.01). Clinical and electrophysiological associations were evident. By 12 months, 16 patients had died or could not continue. In the remainder, relative T2-signal increased over 12 months by 14–29% in right tibialis anterior, right quadriceps, bilateral hamstrings and gastrocnemius/soleus (p < 0.01), independent of onset-site, and paralleled progressive weakness and electrophysiological loss of motor units. Highest clinical, electrophysiological and radiological SRMs were found for revised ALS-functional rating scale scores (1.22), tibialis anterior MUNIX (1.59), and relative T2-weighted leg muscle MR (right hamstrings: 0.98), respectively. Diffusion MR detected minimal changes. Conclusion MUNIX and relative T2-weighted MR represent objective surrogate markers of progressive denervation in MND. Radiological changes were maximal in leg muscles, irrespective of clinical onset-site.

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