scholarly journals Nerve, Muscle, and Synaptogenesis

Cells ◽  
2019 ◽  
Vol 8 (11) ◽  
pp. 1448 ◽  
Author(s):  
Swenarchuk
Keyword(s):  
Experimental Validation ◽  
Synapse Formation ◽  
Current Model ◽  
Neuromuscular Synapse ◽  
Model System ◽  
Integrin Signaling ◽  
Neuromuscular Synapses ◽  
Nerve Muscle ◽  
Postsynaptic Differentiation ◽  
Pericellular Proteolysis

The vertebrate skeletal neuromuscular junction (NMJ) has long served as a model system for studying synapse structure, function, and development. Over the last several decades, a neuron-specific isoform of agrin, a heparan sulfate proteoglycan, has been identified as playing a central role in synapse formation at all vertebrate skeletal neuromuscular synapses. While agrin was initially postulated to be the inductive molecule that initiates synaptogenesis, this model has been modified in response to work showing that postsynaptic differentiation can develop in the absence of innervation, and that synapses can form in transgenic mice in which the agrin gene is ablated. In place of a unitary mechanism for neuromuscular synapse formation, studies in both mice and zebrafish have led to the proposal that two mechanisms mediate synaptogenesis, with some synapses being induced by nerve contact while others involve the incorporation of prepatterned postsynaptic structures. Moreover, the current model also proposes that agrin can serve two functions, to induce synaptogenesis and to stabilize new synapses, once these are formed. This review examines the evidence for these propositions, and concludes that it remains possible that a single molecular mechanism mediates synaptogenesis at all NMJs, and that agrin acts as a stabilizer, while its role as inducer is open to question. Moreover, if agrin does not act to initiate synaptogenesis, it follows that as yet uncharacterized molecular interactions are required to play this essential inductive role. Several alternatives to agrin for this function are suggested, including focal pericellular proteolysis and integrin signaling, but all require experimental validation.

scholarly journals Nerve, Muscle and Synaptogenesis

2019 ◽  
Author(s):  
Lauren Swenarchuk
Keyword(s):  
Experimental Validation ◽  
Synapse Formation ◽  
Current Model ◽  
Neuromuscular Synapse ◽  
Model System ◽  
Integrin Signaling ◽  
Neuromuscular Synapses ◽  
Nerve Muscle ◽  
Postsynaptic Differentiation ◽  
Pericellular Proteolysis

The vertebrate skeletal neuromuscular junction (NMJ) has long served as a model system for studying synapse structure, function and development. Over the last several decades a neuron-specific isoform of agrin, a heparan sulfate proteoglycan, has been identified as playing a central role in synapse formation at all vertebrate skeletal neuromuscular synapses. While agrin was initially postulated to be the inductive molecule that initiates synaptogenesis, this model has been modified in response to work showing that postsynaptic differentiation can develop in the absence of innervation, and that synapses can form in transgenic mice in which the agrin gene is ablated. In place of a unitary mechanism for neuromuscular synapse formation, studies in both mice and zebrafish have led to the proposal that two mechanisms mediate synaptogenesis, with some synapses being induced by nerve contact while others involve the incorporation of prepatterned postsynaptic structures. Moreover, the current model also proposes that agrin can serve two functions, to induce synaptogenesis and to stabilize new synapses, once these are formed. This review examines the evidence for these propositions, and concludes that it remains possible that a single molecular mechanism mediates synaptogenesis at all NMJs, and that agrin acts as a stabilizer, while its role as inducer is open to question. Moreover, if agrin does not act to initiate synaptogenesis, it follows that as yet uncharacterized molecular interactions are required to play this essential inductive role. Several alternatives to agrin for this function are suggested, including focal pericellular proteolysis and integrin signaling, but all require experimental validation.

scholarly journals GA-Binding Protein Is Dispensable for Neuromuscular Synapse Formation and Synapse-Specific Gene Expression

2007 ◽  
Vol 27 (13) ◽  
pp. 5040-5046 ◽  
Author(s):  
Alexander Jaworski ◽  
Cynthia L. Smith ◽  
Steven J. Burden
Keyword(s):  
Gene Expression ◽  
Synapse Formation ◽  
Binding Protein ◽  
Neuromuscular Synapse ◽  
Specific Gene ◽  
Promoter Regions ◽  
Specific Gene Expression ◽  
Muscle Gene Expression ◽  
Synaptic Region ◽  
Ga Binding Protein

ABSTRACT The mRNAs encoding postsynaptic components at the neuromuscular junction are concentrated in the synaptic region of muscle fibers. Accumulation of these RNAs in the synaptic region is mediated, at least in part, by selective transcription of the corresponding genes in synaptic myofiber nuclei. The transcriptional mechanisms that are responsible for synapse-specific gene expression are largely unknown, but an Ets site in the promoter regions of acetylcholine receptor (AChR) subunit genes and other “synaptic” genes is required for synapse-specific transcription. The Ets domain transcription factor GA-binding protein (GABP) has been implicated to mediate synapse-specific gene expression. Inactivation of GABPα, the DNA-binding subunit of GABP, leads to early embryonic lethality, preventing analysis of synapse formation in gabpα mutant mice. To study the role of GABP at neuromuscular synapses, we conditionally inactivated gabpα in skeletal muscle and studied synaptic differentiation and muscle gene expression. Although expression of rb, a target of GABP, is elevated in muscle tissue deficient in GABPα, clustering of synaptic AChRs at synapses and synapse-specific gene expression are normal in these mice. These data indicate that GABP is dispensable for synapse-specific transcription and maintenance of normal AChR expression at synapses.

scholarly journals A novel synaptic plasticity rule explains homeostasis of neuromuscular transmission

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Gilles Ouanounou ◽  
Gérard Baux ◽  
Thierry Bal
Keyword(s):  
Muscle Cell ◽  
Neurotransmitter Release ◽  
Neuromuscular Transmission ◽  
Ex Vivo ◽  
Neuromuscular Synapse ◽  
Skeletal Muscle Cell ◽  
Synaptic Potentiation ◽  
Cell Excitability ◽  
Nerve Muscle ◽  
Retrograde Signal

Excitability differs among muscle fibers and undergoes continuous changes during development and growth, yet the neuromuscular synapse maintains a remarkable fidelity of execution. Here we show in two evolutionarily distant vertebrates (Xenopus laevis cell culture and mouse nerve-muscle ex-vivo) that the skeletal muscle cell constantly senses, through two identified calcium signals, synaptic events and their efficacy in eliciting spikes. These sensors trigger retrograde signal(s) that control presynaptic neurotransmitter release, resulting in synaptic potentiation or depression. In the absence of spikes, synaptic events trigger potentiation. Once the synapse is sufficiently strong to initiate spiking, the occurrence of these spikes activates a negative retrograde feedback. These opposing signals dynamically balance the synapse in order to continuously adjust neurotransmitter release to a level matching current muscle cell excitability.

scholarly journals Unstressing intemperate models: how cold stress undermines mouse modeling

2012 ◽  
Vol 209 (6) ◽  
pp. 1069-1074 ◽  
Author(s):  
Christopher L. Karp
Keyword(s):  
Cold Stress ◽  
Biomedical Research ◽  
Current Model ◽  
Environmental Variable ◽  
Model System ◽  
Laboratory Mice ◽  
Therapeutic Approaches ◽  
Mechanistic Analysis ◽  
Mouse Modeling

Mus musculus enjoys pride of place at the center of contemporary biomedical research. Despite being the current model system of choice for in vivo mechanistic analysis, mice have clear limitations. The literature is littered with examples of therapeutic approaches that showed promise in mouse models but failed in clinical trials. More generally, mice often provide poor mimics of the human diseases being modeled. Available data suggest that the cold stress to which laboratory mice are ubiquitously subjected profoundly affects mouse physiology in ways that impair the modeling of human homeostasis and disease. Experimental attention to this key, albeit largely ignored, environmental variable is likely to have a broad transformative effect on biomedical research.

Pharmacological Properties of Excitatory Neuromuscular Synapses in the Locust

1968 ◽  
Vol 49 (2) ◽  
pp. 341-361
Author(s):  
P. N. R. USHERWOOD ◽  
P. MACHILI
Keyword(s):  
Muscle Fibres ◽  
Amino Group ◽  
Mechanical Responses ◽  
Neuromuscular Synapses ◽  
Level Of Activity ◽  
Excitatory Activity ◽  
Wide Range ◽  
Nerve Muscle ◽  
Related Compounds ◽  
Stimulation Of

1. The effects of a wide range of amino acids and related compounds on retractor unguis nerve-muscle preparations from the locust, grasshopper and cockroach have been investigated. 2. L-glutamate is the most active excitatory substance. The presence of two acidic groups and one amino group is essential for excitatory activity while the position of the amino group is of some importance in determining the level of activity. 3. When L-glutamate is applied iontophoretically to the muscle fibres, ‘glutamate’ depolarizations are recorded only at the synaptic sites. Other evidence that the action of glutamate is restricted to the synaptic sites is presented. 4. Perfusion of isolated locust retractor unguis nerve-muscle preparations with locust haemolymph does not markedly affect the neurally evoked mechanical responses. It appears that locust haemolymph contains little ‘free’ L-glutamate. 5. Four acidic amino aids have been identified in the perfusate from isolated retractor unguis preparations namely, glycine, alanine, aspartate and L-glutamate. However, only L-glutamate increases in concentration during stimulation of the retractor unguis nerve.

Properties of Short-Term Synaptic Depression at Larval Neuromuscular Synapses in Wild-Type and Temperature-Sensitive Paralytic Mutants of Drosophila

2005 ◽  
Vol 93 (5) ◽  
pp. 2396-2405 ◽  
Author(s):  
Ying Wu ◽  
Fumiko Kawasaki ◽  
Richard W. Ordway
Keyword(s):  
Neurotransmitter Release ◽  
Functional Characterization ◽  
Neuromuscular Synapse ◽  
Synaptic Depression ◽  
Temperature Sensitive ◽  
Short Term ◽  
Low Frequencies ◽  
Neuromuscular Synapses ◽  
The Impact

The larval neuromuscular synapse of Drosophila serves as an important model for genetic and molecular analysis of synaptic development and function. Further functional characterization of this synapse, as well as adult neuromuscular synapses, will greatly enhance the impact of this model system on our understanding of synaptic transmission. Here we describe a form of short-term synaptic depression observed at larval, but not adult, neuromuscular synapses and explore the underlying mechanisms. Larval neuromuscular synapses exhibited a form of short-term depression that was strongly dependent on stimulation frequency over a narrow range of low frequencies (0.1–1 Hz). This form of synaptic depression, referred to here as low-frequency short-term depression (LF-STD), results from an activity-dependent reduction in neurotransmitter release. However, in contrast to the predictions of depletion models, the degree of depression was independent of the initial level of neurotransmitter release over a range of extracellular calcium concentrations. This conclusion was confirmed in two temperature-sensitive (TS) paralytic mutants, cacophony and shibire, which exhibit reduced neurotransmitter release resulting from conditional disruption of presynaptic calcium channels and dynamin, respectively. Higher stimulation frequencies (40 or 60 Hz) produced two components of depression that appeared to include LF-STD as well as a more conventional component of short-term depression. These findings reveal novel properties of short-term synaptic depression and suggest that complementary genetic analysis of larval and adult neuromuscular synapses will further define the in vivo mechanisms of neurotransmitter release and short-term synaptic plasticity.

Sign in / Sign up

Export Citation Format

Share Document