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1Departments of Physiology and 2Neurology, Emory University School of Medicine, Atlanta, Georgia 30322
Submitted 17 February 2004; accepted in final form 15 March 2004
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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). Adding to the uncertainty is recent evidence that exercise can extend somewhat the survival of transgenic mice that express SOD1 enzyme mutations that are also found in some cases of human familial ALS (Kirkinezos et al. 2003). In Parkinson's Disease, there is evidence that physical activity may be beneficial, and that lack of activity may be detrimental (Tillerson et al. 2002), and cognitive activity is thought to reduce the risk of Alzheimer's disease (Snowdon et al. 2000). It is not known, however, whether any of this evidence reflects advantages or disadvantages of electrical activity in neuronal populations that eventually degenerate.
In a canine model of inherited motor neuron disease (hereditary canine spinal muscular atrophy, HCSMA), we found previously that slow motor units exhibit dysfunction before other motor-unit types (Pinter et al. 1995) and that type 1 muscle fibers (which populate slow motor units) show dener-vation atrophy before other fiber types (Balice-Gordon et al. 2000). Because slow-type motor units are generally more active during reflex and voluntary motor tasks (Henning and Lomo 1985), we reasoned that motor-unit activity or, more specifically, motor neuron activity, may play a role in the pathogenesis of HCSMA. To test this idea, synergist muscles of the medial gastrocnemius (MG) muscle were denervated in HCSMA homozygotes. In previous studies of normal quadrupeds (cats), synergist denervation has been shown to increase motor neuron activity as reflected by increases of electromyographic (EMG) activity (Pearson et al. 1999). This effect occurs because the MG muscle is solely responsible for ankle extension after synergist denervation. The results of this study demonstrate that MG synergist denervation accelerated MG motor-unit dysfunction and provoked widespread denervation and degeneration of motor axons and motor terminals.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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HCSMA animals were bred specially from a colony maintained at Emory University. Age-matched, normal animals were purchased commercially (Marshall Farms, NY). Presumptive homozygotes are identified by 10 wk of age based on the appearance of muscle weakness in tail and paravertebral muscles. Synergist denervation of the left MG muscle was performed at 
90 days of age in two HCSMA homozygotes and in two normal animals. This age was selected because MG motor-unit failure typically appears between 90 and 120 days (Rich et al. 2002a) and the main intent of this study was to determine whether MG synergist denervation was capable of accelerating these functional changes.
Under general anesthesia (isofluorane), the nerves innervating the main synergists of the MG muscle (FDS, flexor digitalis superficialis; LG, lateral gastrocnemius) were located, severed, and resected in the left hindlimb of homozygote and normal animals. Denervated muscles remained in place. The opposite limb remained intact. After recovery, animals were returned to cage runs. All operated animals resumed walking and showed use of the operated limb within hours after surgery. After 4 wk (2 homozygotes) or 5 wk (2 normal animals), terminal studies were performed in which motor-unit and immunolabeling data were collected from the MG muscles on both sides. All procedures were approved by the Institutional Animal Care and Use Committee at Emory University.
Electrophysiology
Terminal studies were conducted under pentobarbital general anesthesia (initial dose, 45 mg/kg iv), supplemented intravenous asneeded to maintain an absence of corneal and forelimb pinch withdrawal reflexes. Antidromically activated MG motor axons were identified after MG nerve stimulation using bipolar hook electrodes located 1 cm from the nerve entry point in the MG muscle. Axons were impaled in ventral roots (approximately midway between spinal cord and dural exit) using micropipettes filled with 3 M KCl and were stimulated with 0.5-ms depolarizing pulses to activate motor units (Rich et al. 2002a). Motor-unit force recording was performed as described previously, with tetanic activation tested at stimulation frequencies of 50, 100, 150, and 200 Hz (Pinter et al. 1995; Rich et al. 2002a). Conduction velocities of the main motor axon were determined by dividing the conduction distance between the ventral root impalement site and the peripheral nerve stimulation site by the time interval between the peripheral nerve stimulation onset and the arrival of an antidromic action potential. Conduction latencies for intramuscular portions of motor axons were estimated by first measuring the latency between peripheral nerve stimulation onset and the arrival of the antidromic action potential at the ventral root impalement site. This value was then subtracted from the latency between the ventral root axonal stimulation onset and the onset of the MG motor-unit EMG potential.
Immunolabeling
At the conclusion of each terminal study, blocks of MG muscle tissue were excised from each limb and placed into 4% paraformaldehyde for fixation. Sections (60 µm thickness) containing endplate-rich regions were obtained using a Cyrostat (Leica). Acetylcholine (ACh) receptors in motor endplates were labeled with rhodamine conjugated 
-bungarotoxin (Molecular Probes). Axons and motor terminals were labeled with a mouse monoclonal antibody against the phosphorylated heavy fragment of neurofilament protein (SMI31, 1:400, Sternberger Monoclonal). Labeling was visualized using fluorescein-conjugated secondary antibodies (1:100, Jackson Immunoresearch Laboratories). Synaptic vesicles were labeled using either a mouse polyclonal antibody directed against the SV2 protein (1:100, Developmental Studies Hybridoma Bank, University of Iowa) and fluorescein-conjugated secondary antibodies, or a rabbit polyclonal antibody directed at synaptophysin (1:100, Santa Cruz Biotechnology) and AMCA-conjugated secondary antibodies.
Imaging
z-axis stacks of images at sequential focal planes (0.5-µm separation) were obtained of NMJs using an upright microscope equipped with a motorized stage (Leica). Stacks were deconvolved using a commercially available inverse filter algorithm (ImagePro). Illustrated images are flat plane projections obtained by summing deconvolved image stacks. 
120 endplates were examined per MG muscle for analysis of immunostained NMJs.
Statistics
All statistical comparisons in normal and HCSMA animals were performed between data from the left MG (with synergist denervation) and the right MG (unoperated control). The statistical significance of side-to-side comparisons of percentages was determined using the two-tail Fisher exact test (2 x 2 tables) or the likelihood ratio 
2 test (2 x 3 tables) with commercially available software (Systat). Mean values were compared using two-sample t-test. Mean values are presented ±1 SE.
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RESULTS |
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Synergist denervation increases motor-unit dysfunction
In both homozygotes, maximum MG motor-unit tetanic force was significantly reduced after 4 wk of synergist denervation compared with MG motor-unit force from the opposite, unoperated limb (Fig. 1, A and B, and Table 1). No significant differences of maximum motor-unit force were observed between operated and control MG muscles of the two normal animals with unilateral MG synergist denervation for 5 wk. No significant changes were observed in the average contraction speeds of MG motor units in either homozygotes or in normal animals (data not shown).
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). Previous studies have shown that tetanic failure is caused by reduced neuromuscular transmission (Rich et al. 2002b) rather than failure of motor axon conduction during tetanic activation (Pinter et al. 1995). In both homozygotes, mean tetanic failure increased significantly after synergist denervation (Table 1). No MG motor-unit tetanic failure was observed in normal animals with synergist denervation. These results demonstrate that the progression of MG motor-unit dysfunction in HCSMA homozygotes is accelerated after synergist denervation. Conduction velocity is decreased by synergist denervation
To determine whether MG synergist denervation affected the conduction properties of MG motor axons, we measured the conduction velocities of individual MG motor axons located outside the muscle. When compared with values from the unoperated limb, significant decreases of mean MG axonal conduction velocity were observed in homozygotes after MG synergist denervation (Fig. 2A). In contrast, no significant changes of MG axonal conduction velocity were observed in normal animals studied 5 wk after MG synergist denervation. Measurements were also obtained of the conduction time in intramuscular portions of MG motor axons. In synergist-denervated MG muscles of homozygotes, significant increases in mean intramuscular conduction time occurred, whereas no changes were observed in control animals with 5 wk of MG synergist denervation (Fig. 2B). Intramuscular conduction times include the time needed for muscle fiber synaptic activation, so increases in this time might contribute to the changes observed in homozygote intramuscular conduction times. This is unlikely, however, for several reasons. First, no changes in muscle fiber excitability have been detected in HCSMA homozygotes, and the time course of MG endplate currents in homozygotes is unchanged compared with normal despite significant decreases in average quantal content (Rich et al. 2002a,2002b). Second, immunostaining for neurofilaments provided direct evidence for degenerative changes in homozygote intramuscular axons after MG synergist denervation but not in contralateral, control MG muscles or in normal synergist denervated muscles (Fig. 2, C and D). It thus seems likely that the increases of intramuscular conduction time after synergist denervation of homozygote MG muscles reflect changes in the conduction properties of intramuscular motor axons. Comparison of the relative changes of mean intramuscular conduction times with relative changes in conduction velocity of the main motor axon indicates that conduction slowing was greater in the more distal, intramuscular portions of the axon.
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After completion of motor-unit studies, MG muscles were stained for visualizing motor terminals and endplates. We first compared the extent to which endplates labeled for ACh receptors were occupied by combined motor terminal staining for synaptic vesicles (SV2) and for phosphorylated neurofilament protein. Homozygote MG muscles subjected to 4 wk of synergist denervation exhibited significant decreases in the number of intact NMJs and increases in the number of denervated and partially occupied NMJs relative to contralateral, control MG muscles (Fig. 3). In normal animals that had been subjected to unilateral MG synergist denervation for 5 wk, identical comparisons showed no significant differences of MG NMJ innervation status (data not shown).
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Motor endplates visualized by ACh receptor staining in control MG muscles from homozygotes exhibited bright lines of labeling defining the perimeters of primary synaptic gutters and clear labeling of secondary folds (Fig. 4A1). These features were also observed in all MG muscles of age-matched normal animals and are typical of unmanipulated MG muscles from HCSMA homozygotes of similar age (Balice-Gordon et al. 2000). In contrast, after synergist denervation, many singly innervated endplates in homozygote MG muscles showed a loss of bright perimeter receptor staining and a fragmented appearance (Fig. 4B1). In addition, the spacings between separate endplate arms were diminished or absent compared with endplates of the MG muscles on the unoperated sides. These endplates resemble in appearance those observed in more involved proximal hindlimb muscles of HCSMA homozygotes (Balice-Gordon et al. 2000) but differ significantly from endplates that lose innervation abruptly by nerve crush or section after which uniform staining of ACh receptors and overall structure remain largely intact for relatively long periods (Rich and Lichtman 1989). This suggests that loss of structure within individual overlying motor terminals does not occur synchronously after synergist denervation. The appearance of motor terminal staining associated with fragmented endplates provided further support for this possibility. In some cases, select areas of individual terminals showed no evidence of neurofilament or synaptic vesicle staining, thus exposing underlying ACh receptors (Fig. 3B). In other cases, staining for neurofilament or synaptic vesicles demonstrated nerve terminal locations that were not opposed by detectable ACh receptor staining (arrows, Fig. 4B4), suggesting localized withdrawal of ACh receptors. NMJs could also be found in which nerve terminals exhibited neurofilament staining but little or no synaptic vesicle or ACh receptor staining (data not shown). Because synergist denervation produced a nearly complete loss of intact motor terminal innervation in homozygote MG muscles, variability of staining appearance among NMJs after synergist denervation likely reflects different stages of the same degenerative process rather than evidence for different degenerative processes. These observations provide further evidence that the degenerative process accelerated by synergist denervation evolves nonuniformly within individual terminals.
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Ring-like structures that labeled with antibodies for phosphorylated neurofilaments (arrowheads, Fig. 4B2) were commonly observed in homozygote motor terminals but not in any MG muscle from the normal animals treated with synergist denervation for 5 wk. Synergist denervation significantly increased the fraction of homozygote MG motor terminals exhibiting at least one NF ring (Fig. 4C). Most NF rings (77%) were located within the confines of motor terminals in homozygote MG muscles subjected to synergist denervation whereas almost all rings (97%) were located within terminals in the contralateral, control MG muscles which were clearly less advanced in disease progression (see Table 1 and Fig. 3). This suggests that NF rings are formed initially within motor terminals. Supporting this are observations made in control homozygote MG muscles in which terminals that were otherwise normal in appearance could contain a single NF ring (arrow, Fig. 4D). In homozygote control and synergist denervated MG muscles, NF rings were generally located in close association with robust synaptic vesicle and underlying ACh receptor staining (Fig. 4, B4 and D). NF rings have been found in senile plaques in the early stages of Alzheimer's disease (Dickson et al. 1999) and at proximal axon tips soon after axotomy (King et al. 2001). In the present case, it is conceivable that ring appearance represents a step in a process similar to the neurofilament accumulation that occurs in synaptic terminals after axotomy and is thought to involve decreased neurofilament disassembly, increased transport into synaptic terminals, or both (Meller et al. 1993).
Multiple innervation appears after synergist denervation
Multiply innervated endplates were commonly observed in homozygote MG muscles subjected to synergist denervation (36% in 1 and 24% in the other). In contrast, no multiple innervation was observed in contralateral control homozygote MG muscles or in the MG muscles of normal animals with 5 wk of synergist denervation. The increased incidence of multiply innervated endplates after synergist denervation was statistically significant relative to contralateral, control MG muscles (P < 0.01). Both terminal and nodal sprouts contributed to multiple innervation. Although we did not systematically analyze their relative occurrence, nodal and terminal sprouts appeared to contribute in roughly equal proportions. The emergence of sprouting in homozygote MG muscles with synergist denervation is likely related to the significant losses of intact innervation as well as to decreased synaptic transmission (increased motor-unit failure). Both of these factors will contribute to muscle fiber inactivity, which is a known stimulus for sprouting (Brown and Ironton 1977; Duchen and Strich 1968).
In general appearance, multiply innervated endplates shared many of the features described above for singly innervated NMJs. Thus NF rings were commonly associated with each axon entering endplates, and these were invariably located in close relation to positive staining for synaptic vesicles and underlying ACh receptors (Fig. 5A, 1–4), suggesting that the rings form where the synapse has some release competency.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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). The fact that none of these changes were observed in genetically normal animals after MG synergist denervation shows that these effects are specific to HCSMA. Although MG motor neuron activity was not directly measured in this study, synergist denervation increases MG motor neuron activity in normal cats (Misiaszek and Pearson 2002; Pearson et al. 1999). It thus seems reasonable to conclude that increased motor neuron activity accelerates the pathological changes of HCSMA. It also seems likely that motor neuron activity is a major contributing factor during the natural progression of HCSMA and that slow MG motor units show dysfunction before fast motor units because slow motor units are generally more active than fast units (Henning and Lomo 1985).
Our results provide a potential explanation for the clinical appearance of HCSMA homozygotes. Typically, the first signs of weakness appear in the tail extensor muscles, with neck extensor and paravertebral muscles exhibiting signs of weakness soon thereafter (Cork et al. 1990; Pinter et al. 2001). These muscles may become involved before others because their motor neurons are more active, and consideration of the roles played by these muscles in tail and in trunk posture supports this conclusion.
A variety of pathological processes, related directly or indirectly to the underlying genetic defect, could account for the apparent role of activity in HCSMA. HCSMA motor neurons might possess a defect in the ability to contend with the ionic consequences of action potentials or be unable to provide fundamental metabolic support. Alternatively, activity may produce an accumulating toxic response in motor neurons that eventually causes degeneration. In any of these cases, one would expect that a defective mechanism capable of causing an adverse response to action potential activity would be expressed throughout the motor neuron. The results indicate, however, that the pathological consequences of activity are more apparent in some parts of the motor neuron than in others. For example, motor terminals appeared to exhibit the most destructive changes after synergist denervation, at least when compared with preterminal motor axons (Fig. 3B). Comparisons of axonal conduction velocity slowing outside of muscle with intramuscular conduction time increases suggest that the most distal motor axons are relatively more affected. We did not examine MG motor neuron cell bodies or dendrites in this study, so accelerated degenerative or functional changes at these sites after synergist denervation cannot be excluded. However, observations that MG motor axons continue to support action potential activity (Fig. 1) and remain capable of supporting axonal sprouting as well as synapse formation by sprouts (Fig. 5) suggest that any degenerative changes that might occur in the motor neuron cell body are insufficient to eliminate general support for the motor axon. In addition, the likelihood that the effects of synergist denervation are based on increased motor neuron activity implies that MG motor neurons continued to be activated by synaptic input. This is supported by observations that both homozygotes remained able to support weight at the ankle joints of MG synergist-denervated limbs 4 wk after the denervation surgery. This suggests that any changes that might have occurred in motor neuron dendrites are not sufficient to compromise the ability of synaptic input to activate motor neurons because most of these inputs are located on motor neuron dendrites.
The more extensive involvement of the peripheral components of HCSMA motor neurons after synergist denervation is not unexpected in view of previous studies of the normal disease course. These studies have shown that motor-unit tetanic failure is due to decreased release of ACh from motor terminals rather than to blocked or faulty conduction in motor axons, alterations of muscle fiber excitability or to aberrant accumulations of neurofilaments that are commonly observed in proximal motor axons in HCSMA and other forms of motor neurons disease (Rich et al. 2002a,2002b). Tetanic failure appears and progresses without affecting the postnatal maturation of axonal conduction velocity, indicating that cell body support for axonal maturation remains intact despite the appearance of motor-unit failure (Rich et al. 2002a). This evidence suggests that motor-unit failure arises because of specific functional changes that occur at the motor terminal (Rich et al. 2002b).
These results prompt consideration of motor terminal properties that might facilitate interactions between activity and defective mechanisms and cause dysfunction and destruction before other parts of the motor neuron. One important property of the motor terminal, as well as other synapses, is the occurrence of large amounts of entering Ca2+ during activity. This entry occurs into the relatively small volume of the terminal that also features numerous mitochondria (Sanes and Lichtman 1999). Emerging evidence indicates that mitochondria play an important role in controlling Ca2+ levels at the mammalian motor terminal, particularly during repetitive activation (David and Barrett 2000). Given this collection of features and the known destructive capabilities of dysregulated internal Ca2+ (Krieger and Duchen 2002; Nicholls and Budd 2000), a defect in mitochondrial Ca2+ handling, or in other components of the Ca2+ handling system (Babcock and Hille 1998), might cause motor terminal pathological changes to occur, at least before changes in the preterminal axon. The existence of such a defect might help explain why neurofilament abnormalities appear in close association with parts of the terminal that are differentiated for transmitter release (Figs. 4–5) because these are motor terminal locations where the Ca2+ levels are likely to reach the highest levels during activity. It is conceivable that an activated degenerative process might then propagate retrogradely into the preterminal axon and beyond. This could explain why effects on intramuscular motor axons appear to be relatively greater than more proximal portions of the motor axon as judged by conduction time and velocity measurements. Although Ca2+ dysregulation provides an attractive means for linking activity with degenerative changes at motor terminals, the existence of Ca2+ dysregulation at HCSMA motor terminals remains to be demonstrated, and other possibilities exist to explain this link. Moreover, although our results suggest otherwise, it remains formally possible that all the changes we have observed in distal motor neuron components reflect a more generalized loss of support from the motor neuron cell body. Further experiments designed to test specifically whether action potential activity at HCSMA motor terminals is needed for provoking pathological changes in motor terminals may help to resolve this issue.
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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ACKNOWLEDGMENTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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FOOTNOTES |
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Address for reprint requests and other correspondence: M. J. Pinter, Dept. of Physiology, Emory University School of Medicine, 615 Michael St., Atlanta, GA 30322 (E-mail: mpinter{at}physiol.emory.edu).
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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Balice-Gordon RJ, Smith DB, Goldman J, Cork LC, Shirley A, Cope TC, and Pinter MJ. Functional motor unit failure precedes neuromuscular degeneration in canine motor neuron disease. Ann Neurol 47: 596–605, 2000.[CrossRef][Web of Science][Medline]
Brown MC and Ironton R. Motor neuron sprouting induced by prolonged tetrodotoxin block of nerve action potentials. Nature 265: 459–461, 1977.[CrossRef][Medline]
Cork LC, Price DL, Griffin JW, and Sack G. Hereditary canine spinal muscular atrophy: canine motor neuron disease. Can J Vet Res 54: 77–82, 1990.[Web of Science][Medline]
David G and Barrett EF. Stimulation-evoked increases in cytosolic [Ca(2+)] in mouse motor nerve terminals are limited by mitochondrial uptake and are temperature-dependent. J Neurosci 20: 7290–7296, 2000.
Dickson TC, King CE, McCormack GH, and Vickers JC. Neurochemical diversity of dystrophic neurites in the early and late stages of Alzheimer's disease. Exp Neurol 156: 100–110, 1999.[CrossRef][Web of Science][Medline]
Duchen LW and Strich SJ. The effects of botulinum toxin on the pattern of innervation of skeletal muscle in the mouse. Q J Exp Physiol Cogn Med Sci 53: 84–89, 1968.
Henning R and Lomo T. Firing patterns of motor units in normal rats. Nature 314: 164–166, 1985.[CrossRef][Medline]
King CE, Canty AJ, and Vickers JC. Alterations in neurofilaments associated with reactive brain changes and axonal sprouting following acute physical injury to the rat neocortex. Neuropathol Appl Neurobiol 27: 115–126, 2001.[CrossRef][Web of Science][Medline]
Kirkinezos IG, Hernandez D, Bradley WG, and Moraes CT. Regular exercise is beneficial to a mouse model of amyotrophic lateral sclerosis. Ann Neurol 53: 804–807, 2003.[CrossRef][Web of Science][Medline]
Krieger C and Duchen MR. Mitochondria, Ca(2+) and neurodegenerative disease. Eur J Pharmacol 447: 177–188, 2002.[CrossRef][Web of Science][Medline]
Meller D, Schmidt-Kastner R, and Eysel UT. Immunohistochemical studies on neurofilamentous hypertrophy in degenerating retinal terminals of the olivary pretectal nucleus in the rat. J Comp Neurol 331: 531–539, 1993.[CrossRef][Web of Science][Medline]
Misiaszek JE and Pearson KG. Adaptive changes in locomotor activity following botulinum toxin injection in ankle extensor muscles of cats. J Neurophysiol 87: 229–239, 2002.
Nicholls DG and Budd SL. Mitochondria and neuronal survival. Physiol Rev 80: 315–360, 2000.
Pearson KG, Fouad K, and Misiaszek JE. Adaptive changes in motor activity associated with functional recovery following muscle denervation in walking cats. J Neurophysiol 82: 370–381, 1999.
Pinter MJ, Cope T, Cork LC, Green SL, and Rich MM. Canine motor neuron disease: a view from the motor unit. In: Motor Neurobiology of the Spinal Cord, edited by Cope TC. Boca Raton, FL: CRC, 2001, p. 231–250.
Pinter MJ, Waldeck RF, Wallace N, and Cork LC. Motor unit behavior in canine motor neuron disease. J Neurosci 15: 3447–3457, 1995.[Abstract]
Rich MM and Lichtman JW. In vivo visualization of pre-and postsynaptic changes during synapse elimination in reinnervated mouse muscle. J Neurosci 9: 1781–1805, 1989.[Abstract]
Rich MM, Waldeck RF, Cork LC, Balice-Gordon RJ, Fyffe REW, Wang X, Cope TC, and Pinter MJ. Reduced endplate currents provoke motor unit dysfunction while axonal functional properties mature normally in canine motor neuron disease. J Neurophysiol 88: 3293–3304, 2002a.
Rich MM, Wang X, Cope TC, and Pinter MJ. Reduced quantal content with normal synaptic release time course and depression characterize failure of neuromuscular transmission in canine motor neuron disease. J Neurophysoiol 88: 3305–3314, 2002b.
Sanes JR and Lichtman JW. Development of the vertebrate neuromuscular junction. Annu Rev Neurosci 22: 389–442, 1999.[CrossRef][Web of Science][Medline]
Scarmeas N, Shih T, Stern Y, Ottman R, and Rowland LP. Premorbid weight, body mass, and varsity athletics in ALS. Neurology 59: 773–775, 2002.
Snowdon DA, Greiner LH, and Markesbery WR. Linguistic ability in early life and the neuropathology of Alzheimer's disease and cerebrovascular disease. Findings from the Nun Study. Ann NY Acad Sci 903: 34–38, 2000.[CrossRef][Web of Science][Medline]
Tillerson JL, Cohen AD, Caudle WM, Zigmond MJ, Schallert T, and Miller GW. Forced nonuse in unilateral parkinsonian rats exacerbates injury. J Neurosci 22: 6790–6799, 2002.
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