Acetylcholine negatively regulates development of the neuromuscular junction through distinct cellular mechanisms

An, Mahru C.; Lin, Weichun; Yang, Jiefei; Dominguez, Bertha; Padgett, Daniel; Sugiura, Yoshie; Aryal, Prafulla; Gould, Thomas W.; Oppenheim, Ronald W.; Hester, Mark E.; Kaspar, Brian K.; Ko, Chien Ping; Lee, Kuo Fen

doi:10.1073/pnas.1004956107

Cited by 33 publications

(31 citation statements)

References 52 publications

(65 reference statements)

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“…Genetically silencing ACh synthesis in motor neurons leads to extensive branching of motor neuron axons and hyper-innervation of muscle fibers (Misgeld et al, 2002). Similar effects have been observed in mice where ACh receptors have been deleted (An et al, 2010). These findings support the idea that signaling through postsynaptic ACh receptors inhibits the growth and branching of motor neuron axons.…”

Section: Introductionsupporting

confidence: 77%

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Elimination of Redundant Synaptic Inputs in the Absence of Synaptic Strengthening

Wang¹,

Liu²,

Zhang³

2011

J. Neurosci.

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Synaptic refinement, a developmental process that consists of selective elimination and strengthening of immature synapses, is essential for the formation of precise neuronal circuits and proper brain function. At glutamatergic synapses in the brain, activity-dependent recruitment of AMPA receptors (AMPAR) is a key mechanism underlying the strengthening of immature synapses. Studies using receptor over-expression have shown that the recruitment of AMPARs is subunit specific. With the notable exception of hippocampal CA3-CA1 synapses, however, little is known about how native receptors behave or the roles of specific AMPAR subunits in synaptic refinement in vivo. Using patch-clamp recordings in acute slices, we examined developmental refinement of whisker relay (lemniscal) synapses in the thalamus in mice deficient of AMPAR subunits. Deletion of GluA3 or GluA4 caused significant reductions of synaptic AMPAR currents in thalamic neurons at P16-17, with a greater reduction observed in GluA3-deficient mice. Deletions of both GluA3 and GluA4 abolished synaptic AMPAR responses in the majority of thalamic neurons, indicating that at thalamic relay synapses AMPARs are composed primarily of GluA3 and GluA4. Surprisingly, deletions of GluA3 or GluA4 or both had no effect on the elimination of relay inputs: the majority of thalamic neurons in these knockout mice—as in wild type mice—receive a single relay input. However, experience-dependent strengthening of thalamic relay synapses was impaired in GluA3 knockout mice. Together these findings suggest that the elimination of immature glutamatergic synapses proceeds normally in the absence of synaptic strengthening, and highlight the role of GluA3-containing AMPARs in experience-dependent synaptic plasticity.

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Section: Introductionsupporting

confidence: 77%

“…These findings support the idea that signaling through postsynaptic ACh receptors inhibits the growth and branching of motor neuron axons. However, at least some of these effects appear to be mediated by ACh receptors located on cells other than the muscle (An et al, 2010). …”

Section: Introductionmentioning

confidence: 99%

Elimination of Redundant Synaptic Inputs in the Absence of Synaptic Strengthening

Wang¹,

Liu²,

Zhang³

2011

J. Neurosci.

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“…2A). The gross morphology of the KO neonates was similar to that described for mice with severe defects in muscle differentiation (16), neuromuscular junction (NMJ) formation or function (17)(18)(19), or EC coupling (20)(21)(22)(23). KO neonates were born in expected Mendelian ratios from heterozygous crosses of Stac3-LacZ knockin mice, indicating that Stac3 is not required for embryonic viability (Table S1); however, they were completely paralyzed and died rapidly following birth.…”

Section: Loss Of Stac3mentioning

confidence: 56%

Skeletal muscle-specific T-tubule protein STAC3 mediates voltage-induced Ca ²⁺ release and contractility

Nelson

Liu

et al. 2013

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

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125

169

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Excitation-contraction (EC) coupling comprises events in muscle that convert electrical signals to Ca 2+ transients, which then trigger contraction of the sarcomere. Defects in these processes cause a spectrum of muscle diseases. We report that STAC3, a skeletal muscle-specific protein that localizes to T tubules, is essential for coupling membrane depolarization to Ca 2+ release from the sarcoplasmic reticulum (SR). Consequently, homozygous deletion of src homology 3 and cysteine rich domain 3 (Stac3) in mice results in complete paralysis and perinatal lethality with a range of musculoskeletal defects that reflect a blockade of EC coupling. Muscle contractility and Ca 2+ release from the SR of cultured myotubes from Stac3 mutant mice could be restored by application of 4-chloro-m-cresol, a ryanodine receptor agonist, indicating that the sarcomeres, SR Ca 2+ store, and ryanodine receptors are functional in Stac3 mutant skeletal muscle. These findings reveal a previously uncharacterized, but required, component of the EC coupling machinery of skeletal muscle and introduce a candidate for consideration in myopathic disorders.

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“…However, the mechanisms of synaptic refinement remain incompletely understood. At the neuromuscular junction, silencing of synaptic transmission disrupted the refinement process (13,14). The role of synaptic transmission in the refinement of central synapses seems more complex.…”

mentioning

confidence: 99%

Essential role of postsynaptic NMDA receptors in developmental refinement of excitatory synapses

Zhang

Peterson

Liu

2012

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

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Neurons in the brains of newborns are usually connected with many other neurons through weak synapses. This early pattern of connectivity is refined through pruning of many immature connections and strengthening of the remaining ones. NMDA receptors (NMDARs) are essential for the development of excitatory synapses, but their role in synaptic refinement is controversial. Although chronic application of blockers or global knockdown of NMDARs disrupts developmental refinement in many parts of the brain, the ubiquitous presence of NMDARs makes it difficult to dissociate direct effects from indirect ones. We addressed this question in the thalamus by using genetic mosaic deletion of NMDARs. We demonstrate that pruning and strengthening of immature synapses are blocked in neurons without NMDARs, but occur normally in neighboring neurons with NMDARs. Our data support a model in which activation of NMDARs in postsynaptic neurons initiates synaptic refinement.D uring early development in vertebrates, neurons in many parts of the nervous system form weak synapses with a large number of target cells (1-7). This early pattern of connectivity is refined through two processes: synapse elimination that removes many initial connections and synapse maturation whereby the remaining connections are strengthened (8,9). This refinement of immature synapses is essential for the formation of neural circuits, and provides the basis for behavioral development. Many studies, in particular those conducted at the neuromuscular junction, in the cerebellum and visual pathways, have demonstrated that activity plays a central role in synaptic refinement (10-12). However, the mechanisms of synaptic refinement remain incompletely understood. At the neuromuscular junction, silencing of synaptic transmission disrupted the refinement process (13,14). The role of synaptic transmission in the refinement of central synapses seems more complex. Although manipulations of presynaptic activity disrupted the refinement of connections in the visual pathway (15-17), some of the effects were independent of synaptic transmission (18,19).The vast majority of excitatory synapses in the brain use glutamate as neurotransmitter; synaptic transmission is usually mediated by AMPA receptors (AMPARs) and NMDA receptors (NMDARs) in postsynaptic neurons. NMDARs play an important role in the development of neural circuits. In the brains of neonates, glutamatergic synapses have few or no AMPARs, and synaptic transmission is primarily mediated by NMDARs (20-23). Activation of NMDARs by correlated activity is thought to be a key mechanism underlying synaptic refinement during development (24, 25). Consistent with this idea, chronic application of NMDAR antagonists or global knockdown of NMDARs disrupts developmental refinement of neuronal circuits in many parts of the brain (26-28). However, recent studies in the hippocampus have shown that single-cell deletion of NMDARs in newborn mice has no effect on the number or density of synaptic spines (29). These findings raised the...

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Acetylcholine negatively regulates development of the neuromuscular junction through distinct cellular mechanisms

Cited by 33 publications

References 52 publications

Elimination of Redundant Synaptic Inputs in the Absence of Synaptic Strengthening

Elimination of Redundant Synaptic Inputs in the Absence of Synaptic Strengthening

Skeletal muscle-specific T-tubule protein STAC3 mediates voltage-induced Ca ²⁺ release and contractility

Essential role of postsynaptic NMDA receptors in developmental refinement of excitatory synapses

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Acetylcholine negatively regulates development of the neuromuscular junction through distinct cellular mechanisms

Cited by 33 publications

References 52 publications

Elimination of Redundant Synaptic Inputs in the Absence of Synaptic Strengthening

Elimination of Redundant Synaptic Inputs in the Absence of Synaptic Strengthening

Skeletal muscle-specific T-tubule protein STAC3 mediates voltage-induced Ca 2+ release and contractility

Essential role of postsynaptic NMDA receptors in developmental refinement of excitatory synapses

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Product

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Skeletal muscle-specific T-tubule protein STAC3 mediates voltage-induced Ca ²⁺ release and contractility