Disruption of TrkB-Mediated Signaling Induces Disassembly of Postsynaptic Receptor Clusters at Neuromuscular Junctions

Department of Neuroscience University of Pennsylvania School of Medicine, Philadelphia 19104, USA.
Neuron (Impact Factor: 15.05). 12/1999; 24(3):567-83. DOI: 10.1016/S0896-6273(00)81113-7
Source: PubMed


Neurotrophins and tyrosine receptor kinase (Trk) receptors are expressed in skeletal muscle, but it is unclear what functional role Trk-mediated signaling plays during postnatal life. Full-length TrkB (trkB.FL) as well as truncated TrkB (trkB.t1) were found to be localized primarily to the postsynaptic acetylcholine receptor- (AChR-) rich membrane at neuromuscular junctions. In vivo, dominant-negative manipulation of TrkB signaling using adenovirus to overexpress trkB.t1 in mouse sternomastoid muscle fibers resulted in the disassembly of postsynaptic AChR clusters at neuromuscular junctions, similar to that observed in mutant trkB+/- mice. When TrkB-mediated signaling was disrupted in cultured myotubes in the absence of motor nerve terminals and Schwann cells, agrin-induced AChR clusters were also disassembled. These results demonstrate a novel role for neurotrophin signaling through TrkB receptors on muscle fibers in the ongoing maintenance of postsynaptic AChR regions.

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Available from: Qiang Chang
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    • "It is known that A2A receptors, at motor nerve terminals, trigger the action of BDNF [29], which enhances transmitter release at developing neuromuscular junctions [33], improving neuromuscular transmission in the adult rat diaphragm [34] and facilitating synaptic efficacy by increasing presynaptic depolarization at the neuromuscular junction [35]. BDNF is also important for maintenance of ACh receptor clustering in the endplate [36], [37]. Whether the enhancement by A2A receptor in the pre-symptomatic phase of the disease, could account for the potentiation of endogenous BDNF actions that might occur at the neuromuscular junction, therefore, enhancing synaptic transmission and compensating an eventual early denervation needs to be investigated. "
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    ABSTRACT: Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease leading to motor neuron dysfunction resulting in impairment of neuromuscular transmission. A2A adenosine receptors have already been considered as a potential therapeutical target for ALS but their neuromodulatory role at the neuromuscular junction in ALS remains to be clarified. In the present work, we evaluated the effects of A2A receptors on neuromuscular transmission of an animal model of ALS: SOD1(G93A) mice either in the pre-symptomatic (4-6 weeks old) or in the symptomatic (12-14 weeks old) stage. Electrophysiological experiments were performed obtaining intracellular recordings in Mg2+ paralyzed phrenic nerve-hemidiaphragm preparations. Endplate potentials (EPPs), quantal content (q. c.) of EPPs, miniature endplate potentials (MEPPs) and giant miniature endplate potential (GMEPPs) were recorded. In the pre-symptomatic phase of the disease (4-6 weeks old mice), the selective A2A receptor agonist, CGS 21680, significantly enhanced (p<0.05 Unpaired t-test) the mean amplitude and q.c. of EPPs, and the frequency of MEPPs and GMEPPs at SOD1(G93A) neuromuscular junctions, the effect being of higher magnitude (p<0.05, Unpaired t-test) than age-matched control littermates. On the contrary, in symptomatic mice (12-14 weeks old), CGS 21680 was devoid of effect on both the amplitude and q.c. of EPPs and the frequency of MEPPs and GMEPPs (p<0.05 Paired t-test). The results herein reported clearly document that at the neuromuscular junction of SOD1(G93A) mice there is an exacerbation of A2A receptor-mediated excitatory effects at the pre-symptomatic phase, whereas in the symptomatic phase A2A receptor activation is absent. The results thus suggest that A2A receptors function changes with ALS progression.
    Full-text · Article · Aug 2014 · PLoS ONE
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    No preview · Article · May 2014 · Journal of Neuroscience Research
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    • "Age-related changes in myelinated Schwann cells have also been reported and might be associated with NMJ degeneration [100]. It has interestingly been shown that neurotrophic and myotrophic factors such as BDNF, NT-3, insulin-like growth factor (IGF)-I, and IGF-II, which are necessary for the maintenance of presynaptic and postsynaptic apparatus at the NMJ, also play a modulating role in aging [101, 102]. For example, IGF-1 injections into muscle inhibit motor neuron and NMJ degeneration and prevent age-related force decline in mice [103]. "
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