Agrin Involvement in Synaptogenesis Induced by Exercise in a Rat Model of Experimental Stroke
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Background Agrin is a proteoglycan that aggregates nicotinic acetylcholine receptors (AChRs) on neuromuscular junctions and takes part in synaptogenesis in the development of the central nervous system. However, its effects on neural repair and synaptogenesis after stroke are still unclear. Objective This study aimed to investigate the effects of agrin on neural repair and synaptogenesis after stroke and the effects of exercise on this process in vivo and in vitro. Methods Exercise with gradually increased intensity was initiated at 1 day after middle cerebral artery occlusion (MCAO) for a maximum of 14 days. Neurological deficit scores and foot fault tests were used to assess the behavioral recovery. Western blotting, immunofluorescence, and electron microscopic images were used to detect the expression of agrin, synaptogenesis-related proteins, and synaptic density in vivo. In vitro, the ischemic neuron model was established via oxygen-glucose deprivation (OGD). The lentivirus overexpressed agrin and CREB inhibitor were used to investigate the mechanism by which agrin promoted synaptogenesis. Results Exercise promoted behavioral recovery and this beneficial role was linked to the upregulated expression of agrin and increased synaptic density. Overexpressed agrin promoted synaptogenesis in OGD neuron, CREB inhibitor downregulated the expression of agrin and hampered synaptogenesis in cultured neurons. Conclusions These results indicated that exercise poststroke improved the recovery of behavioral function after stroke. Synaptogenesis was an important and beneficial factor, and agrin played a critical role in this process and could be a potential therapeutic target for the treatment of stroke and other nervous system diseases.Keywords:
Synaptogenesis
Agrin
Purpose: Myasthenia gravis (MG) is an antibody-mediated autoimmune disease of the neuromuscular junction (NMJ) that causes impaired neuromuscular transmission and muscle weakness. Muscle Specific Kinase (MuSK) is recognized as the auto-antigen in about 10% of MG patients. Activation of MuSK by neural agrin is essential for acetylcholine receptor (AChR) clustering at the NMJ. Here we aimed to define the mechanisms by which anti-MuSK antibodies interfere with the postsynaptic AChR cluster.Conclusion: Anti-MuSK auto-antibodies cross-link and activate MuSK. This somehow causes the disassembly of large pre-existing AChR clusters.
Agrin
Neuromuscular transmission
Muscle weakness
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Pathogenesis
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The structure and function of a mature neuromuscular junction (NMJ) is maintained by nerve-derived factors and muscular activity. When muscle contracts upon neural stimulation, ATP is co-released with acetylcholine from motor nerve endings. Recent studies indicate that ATP regulates post-synaptic gene expression, such as acetylcholinesterase (AChE) and acetylcholine receptor (AChR), via P2Y1 receptors that co-localize with AChRs at the NMJs. In order to determine the role of ATP and P2Y1 receptor in modulating the post-synaptic specializations, I investigated the role of ATP and its P2Y1 nucleotide receptors in agrin-induced AChR aggregation in cultured myotubes. By adopting drug treatment and over-expression approaches, I demonstrated that ATP and P2Y1 receptor potentiated the agrin-in...[ Read more ]
Agrin
Motor Endplate
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Neuromuscular junctions (NMJs) normally form in the central region of developing muscle. In this process, agrin released from motor neurons has been considered to initiate the formation of synaptic acetylcholine receptor (AChR) clusters (neurocentric model). However, in muscle developing in the absence of nerves and thus of agrin, AChR clusters still form in the muscle center. This raises the possibility that the region of NMJ formation is determined by muscle-derived cues that spatially restrict the nerve to form synapses from aneural AChR clusters, e.g., by patterned expression of the agrin receptor MuSK (muscle-specific kinase) (myocentric model). Here we examine at initial stages of synaptogenesis whether the responsiveness of myotubes to agrin is spatially restricted, whether the regions of NMJ formation in wild-type muscle and of aneural AChR cluster formation in agrin-deficient animals correlate, and whether AChR cluster growth depends on the presence of agrin. We show that primary myotubes form AChR clusters in response to exogenous agrin in their central region only, a pattern that can spatially restrict NMJ formation. However, the nerve also makes synapses in regions in which aneural AChR clusters do not form, and agrin promotes synaptic cluster growth from the first stages of neuromuscular contact formation. These data indicate that aneural AChR clusters per se are not required for NMJ formation. A model is proposed that explains either the neurocentric or the myocentric mode of NMJ formation depending on a balance between the levels of MuSK expression and the availability of nerve-released agrin.
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Synaptogenesis
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Agrin
Repetitive nerve stimulation
Neuromuscular transmission
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Abstract The increasing understanding of the structural complexity of the neuromuscular junction (NMJ), and the processes that are important in its development, suggests many possible new disease targets. Here, we summarize briefly the genetic and autoimmune disorders that affect neuromuscular transmission, and the identified targets, including new evidence that antibodies to muscle‐specific receptor tyrosine kinase (MuSK) are involved in the pathogenesis of acetylcholine receptor (AChR) antibody–negative myasthenia gravis. We then review the development of the NMJ, focusing on the important roles of nerve‐derived agrin and MuSK in clustering of AChRs and other essential components of the NMJ. © 2002 John Wiley & Sons, Inc. Muscle Nerve 25: 4–16, 2002
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Neuromuscular transmission
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Here we present the first evidence that muscle-specific kinase (MuSK) antigen can cause myasthenia in animals. MuSK is expressed at the postsynaptic membranes of neuromuscular junctions (NMJ) and forms complexes with acetylcholine receptors (AChR) and rapsyn. MuSK is activated by agrin, which is released from motoneurons, and induces AChR clustering and subsequent formation of NMJ in embryos. Notably, autoantibodies against MuSK were found in a proportion of patients with generalized myasthenia gravis (MG) but without the characteristic AChR autoantibodies. However, MuSK autoantibodies had no known pathogenic potential, and animals immunized with purified MuSK proteins did not develop MG in former studies. In contrast, we have now injected rabbits with MuSK ectodomain protein in vivo and evoked a MG-like muscle weakness with a reduction of AChR clustering at the NMJ. Our results showed that MuSK is required for maintenance of synapses and that interference with that function by MuSK antibodies causes myasthenic weakness. In vitro, AChR clustering in myotubes is induced by agrin and agrin-independent inducers, which do not activate MuSK. Neither the receptor nor the activation mechanisms of AChR clustering induced by agrin-independent inducers has been identified with certainty, but MuSK autoantibodies in myasthenic animals inhibited both agrin and agrin-independent AChR clustering. MuSK plays multiple roles in pre-patterning of the postsynaptic membrane before innervation and formation of NMJ in embryos. Some of these mechanisms may also participate in the maintenance of mature NMJ. This model system would provide new knowledge about the molecular pathogenesis of MG and MuSK functions in mature NMJ.
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Agrin and its receptor MuSK are required for the formation of the postsynaptic apparatus at the neuromuscular junction (NMJ). In the current model the local deposition of agrin by the nerve and the resulting local activation of MuSK are responsible for creating and maintaining the postsynaptic apparatus including clusters of acetylcholine receptors (AChRs). Concomitantly, the release of acetylcholine (ACh) and the resulting depolarization disperses those postsynaptic structures that are not apposed by the nerve and thus not stabilized by agrin-MuSK signaling. Here we show that a miniaturized form of agrin, consisting of the laminin-binding and MuSK-activating domains, is sufficient to fully restore NMJs in agrin mutant mice when expressed by developing muscle. Although miniagrin is expressed uniformly throughout muscle fibers and induces ectopic AChR clusters, the size and the number of those AChR clusters contacted by the motor nerve increase during development. We provide experimental evidence that this is due to ACh, because the AChR agonist carbachol stabilizes AChR clusters in organotypic cultures of embryonic diaphragms. In summary, our results show that agrin function in NMJ development requires only two small domains, and that this function does not depend on the local deposition of agrin at synapses. Finally, they suggest a novel local function of ACh in stabilizing postsynaptic structures.
Agrin
Synaptic cleft
Motor Endplate
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Agrin
Neuromuscular transmission
Muscle weakness
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