Synaptic dynamics at the neuromuscular junction: Mechanisms and models

Essen, David C. Van; Gordon, Herman; Soha, James M.; Fraser, Scott E.

doi:10.1002/neu.480210115

Cited by 70 publications

(31 citation statements)

References 59 publications

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“…This question emerges out of a CNTF Regulates Synapse Elimination DevNeurosci 1996;18:185-198 long-held belief that synapse elimination is a competitive process, i.e., synapses compete for a trophic substance that is supplied by the target cells in limited amounts [recent reviews : Betz et al, 1990;Lichtman and BaliceGordon, 1990;Herrera and Werle. 1990;Van Essen et al, 1990;Colman and Lichtman, 1993]. The results of three different experiments described in this report indi cate that CNTF delivered during synapse elimination in the LA muscle results in 2 -3 times more multiple inner vation than normal.…”

Section: Discussionmentioning

confidence: 61%

Ciliary Neurotrophic Factor May Act in Target Musculature to Regulate Developmental Synapse Elimination

Jordan

1996

Dev Neurosci

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During development of mammalian skeletal muscles, synaptic contacts from different motoneurons are made on to individual muscle fibers but then are progressively lost until the adult pattern of single innervation is established. Although this process of synapse elimination occurs throughout the developing nervous system, little is known about the underlying mechanisms that drive this process. Competition for target-derived trophic substances has been proposed as one mechanism whereby synapses are selectively maintained or eliminated. To directly test whether exogenous trophic substance could alter neuromuscular synapse elimination, levator ani (LA) muscles of male rats were treated during the period of synapse elimination with either human recombinant ciliary neurotrophic factor (CNTF – a putative motoneuronal survival factor), or vehicle. LA muscles were stained with tetranitroblue tetrazolium at the end of treatment and the number of axonal inputs per muscle fiber was quantified. Effects of CNTF on other parameters such as body weight, axonal sprouting, muscle fiber and motoneuronal growth were also assessed. CNTF-treated muscles contained 3 times more multiple innervation than did vehicle-treated muscles, suggesting that CNTF can regulate synapse elimination in the LA. Moreover, CNTF delivered near the LA was more potent in blocking synapse elimination than the same dose of CNTF delivered at a site distant from the LA, suggesting that the target muscle is an important site, either for direct CNTF action on synapse elimination, and/or for directed transport of CNTF to motoneuronal cell bodies.

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Section: Discussionmentioning

confidence: 61%

Ciliary Neurotrophic Factor May Act in Target Musculature to Regulate Developmental Synapse Elimination

Jordan

1996

Dev Neurosci

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“…In our experiments, relatively high concentrations (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25) pM) of the calpain I inhibitor produced synapse reduction even in the absence of stimulation. (There was a modest, statistically nonsignificant tendency for leupeptin, cystatin, and aprotinin to do this also.)…”

Section: Discussionmentioning

confidence: 64%

“…These molecules may be involved in important processes such as neurite outgrowth (3), synaptic plasticity (4), and degeneration due to age or injury in the nervous system (5). The action of calcium-activated proteases has been put forward (6-8) as one of several hypotheses for the basis of activity-dependent synapse reduction at the neuromuscular junction (9).To further investigate the molecular mechanisms involved in activity-dependent synapse reduction, we developed an in vitro model by forming neuromuscular junctions in a threecompartment chamber culture system. Our previous results showed that in this culture system, cholinergic synaptic connections were reduced by about 50% after 24 hr of stimulation (10), indicating that the synapse reduction in this system is activity-dependent.…”

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confidence: 99%

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Proteolytic action of thrombin is required for electrical activity-dependent synapse reduction.

Liu

Fields

Festoff

et al. 1994

Proc. Natl. Acad. Sci. U.S.A.

142

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Molecular anisms of activity-dependent synapse reduction were studied In an in vitro mam an neuromuscular preparation. Synapse reduction in this model is activity-dependent and is substantially reduced by the broadSpectruID protease Inhibitor, leupeptin, suging the role of activity-dependent proteolytic action in the process. Our present experiments show that a potent and specific thrombin inhibitor, hirudin, at nanomoar concentration completely blocked the activity-dependent synapse reduction. Furthermore, a naturally occuing serine protease inhibitor, protease nexin I (PNI), which closely colocalize with acetylchoflne receptors at the neuromuscular junction, inhibited the synapse reduction at the same low concentration. In contrast, neither cystatin, a cysteine protease inhibitor, nor aproti-n, a serine protease inhibitor that does not inhibit thrombin, blocked the synapse reduction.Simiiariy, neither of the inhibitors of the calcium-activated proteases calpain I and H prevented the reduction of synapses. These results starngly s t that serine proteolytic action by thrombin or thrombin-like molecules is required for synapse reduction in our in vitro model ofthe mammalian neuromuscular jcion.Synapse remodeling is a critical process during development of the nervous system and neuromuscular junction (1). This remodeling involves a substantial reduction, typically 40%, of the synapses initially established. Although it has long been known that this process is activity-dependent (2), the cellular and molecular mechanism of the process is not yet clear.Recently, increasing evidence suggests that some endogenous proteases and protease inhibitors might participate in the regulation of development of the central and peripheral nervous system. These molecules may be involved in important processes such as neurite outgrowth (3), synaptic plasticity (4), and degeneration due to age or injury in the nervous system (5). The action of calcium-activated proteases has been put forward (6-8) as one of several hypotheses for the basis of activity-dependent synapse reduction at the neuromuscular junction (9).To further investigate the molecular mechanisms involved in activity-dependent synapse reduction, we developed an in vitro model by forming neuromuscular junctions in a threecompartment chamber culture system. Our previous results showed that in this culture system, cholinergic synaptic connections were reduced by about 50% after 24 hr of stimulation (10), indicating that the synapse reduction in this system is activity-dependent. A protease inhibitor, leupeptin, at 10 nM concentration, blocked more than 60%o of the activity-dependent synapse reduction (11), suggesting that proteolytic action is involved in the process. We now report that the application of a variety of protease inhibitors to this model system shows that thrombin is an essential mediator of activity-dependent synapse reduction at these neuromuscularjunctions. Preliminary reports of this work have appeared (12, 13). MATERIALS AND METHODSCell Culture. ...

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“…Second, the overall rate of decay might increase with a cell's average degree of activation, which in turn would increase with the total synaptic strength received by a cell. Increased activation could increase release of a molecule that degrades synapses, such as a protease, or decrease release of a molecule that supports synapses, such as a trophic, adhesion, or sprouting factor (evidence for such mechanisms is reviewed in Van Essen et al 1990). Increased activation might also increase decay due to thresholds for synaptic modification, as just discussed.…”

Section: Use Ofmentioning

confidence: 99%

The Role of Constraints in Hebbian Learning

1994

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Models of unsupervised, correlation-based (Hebbian) synaptic plasticity are typically unstable: either all synapses grow until each reaches the maximum allowed strength, or all synapses decay to zero strength. A common method of avoiding these outcomes is to use a constraint that conserves or limits the total synaptic strength over a cell. We study the dynamic effects of such constraints.Two methods of enforcing a constraint are distinguished, multiplicative and subtractive. For otherwise linear learning rules, multiplicative enforcement of a constraint results in dynamics that converge to the principal eigenvector of the operator determining unconstrained synaptic development. Subtractive enforcement, in contrast, typically leads to a final state in which almost all synaptic strengths reach either the maximum or minimum allowed value. This final state is often dominated by weight configurations other than the principal eigenvector of the unconstrained operator. Multiplicative enforcement yields a "graded" receptive field in which most mutually correlated inputs are represented, whereas subtractive enforcement yields a receptive field that is "sharpened" to a subset of maximally correlated inputs. If two equivalent input populations (e.g., two eyes) innervate a common target, multiplicative enforcement prevents their segregation (ocular dominance segregation) when the two populations are weakly correlated; whereas subtractive enforcement allows segregation under these circumstances.These results may be used to understand constraints both over output cells and over input cells. A variety of rules that can implement constrained dynamics are discussed.Development in many neural systems appears to be guided by "Hebbian" or similar activity-dependent, correlation-based rules of synaptic modification (reviewed in Miller 1990a). Several lines of reasoning suggest 'Current address: Departments of Physiology and Otolaryngology, University of 'Current address: Radio Astronomy,

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Synaptic dynamics at the neuromuscular junction: Mechanisms and models

Cited by 70 publications

References 59 publications

Ciliary Neurotrophic Factor May Act in Target Musculature to Regulate Developmental Synapse Elimination

Ciliary Neurotrophic Factor May Act in Target Musculature to Regulate Developmental Synapse Elimination

Proteolytic action of thrombin is required for electrical activity-dependent synapse reduction.

The Role of Constraints in Hebbian Learning

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