Competitive mechanisms underlying synapse elimination in the lumbrical muscle of the rat

Betz, William J.; Ribchester, Richard R.; Ridge, R. M. A. P.

doi:10.1002/neu.480210102

Cited by 44 publications

(23 citation statements)

References 36 publications

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“…Neonatal synapse elimination is a competitive (Betz et al, 1989;Balice-Gordon and Lichtman, 1994) and activity-dependent (O'Brien et al, 1978;Thompson, 1985;Busetto et al, 2000) process by which all but one of the multiple nerve terminals are eliminated from the NMJ (for review, see Sanes and Lichtman, 1999). We found that synapse elimination was significantly delayed in the NCAM null semitendinosus muscle, as also observed for the sternomastoid muscle (Moscoso et al, 1998).…”

Section: Neonatal Synapse Elimination Is Delayed In Ncam Null Junctionssupporting

confidence: 53%

Structural and Functional Alterations of Neuromuscular Junctions in NCAM-Deficient Mice

2000

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The role of neural cell adhesion molecule (NCAM) in the development and maturation of the neuromuscular junction (NMJ) was explored by characterizing structurally and functionally NMJs from postnatal day 11 (P11) to P30 ϩ/ϩ, ϩ/Ϫ, and Ϫ/Ϫ NCAM null mutant mice. Differences in NCAM levels resulted in alterations in the size and shape of NMJs, with Ϫ/Ϫ NMJs being smaller. Additionally both the withdrawal of polyneuronal innervation and the selective accumulation of synaptic vesicle protein in the presynaptic terminal were delayed. These observations suggest that the bidirectional signaling responsible for these events is impaired at Ϫ/Ϫ NMJs. Functionally, miniature end plate potential size, end plate potential size, and quantal content did not differ from that of wild type under either normal or low release conditions. However at normal release conditions, Ϫ/Ϫ NMJs, unlike ϩ/ϩ NMJs, lacked paired-pulse facilitation. The most striking abnormality was the inability of NCAM null junctions to maintain transmitter output with repetitive stimuli. Combined electrophysiological and FM1-43-labeling studies suggest that NCAM null junctions are unable either to dock or to mobilize a sufficient number of vesicles at high but physiological rates of transmitter release. Taken together our observations show that many aspects of transmission are normal and, thus, that many presynaptic and postsynaptic molecules have assembled properly in the absence of NCAM. However, the fact that NCAM was required for specific aspects of transmission, including pairedpulse facilitation and reliable transmission with repetitive stimuli, suggests that NCAM either is directly involved in these processes or is required for the proper organization and/or function of other molecules underlying these processes. Key words: NCAM; synaptic depression; FM1-43; synapse elimination; neuromuscular transmission; synapse maturationFor proper nervous system function, developing neurons must grow to, and form connections with, their appropriate targets. Subsequent interactions transform these initial connections into highly specialized synapses (for review, see Sanes and Lichtman, 1999). During development of the neuromuscular junction (NMJ), synaptic vesicles that are initially distributed along the length of the motor axon become clustered at presynaptic active zones (Kelly and Zacks, 1969;Lupa and Hall, 1989;Dahm and Landmesser, 1991). Postsynaptically, the density of acetylcholine receptors (AChRs) increases dramatically both by the clustering of diffusely distributed AChRs (Anderson and Cohen, 1977;Frank and Fischbach, 1979;Nitkin et al., 1987) and by transcriptional activation of AChR genes in subsynaptic myonuclei (Usdin and Fischbach, 1986;Fischbach and Rosen, 1997). Postnatally, as the muscle fibers grow, the shape and complexity of the NMJ change, with small uniform plaques of AChRs expanding into pretzel-shaped structures as the nerve terminal grows (Balice-Gordon and Lichtman, 1990). Additionally, there is a withdrawal of all but one motor axon from t...

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Section: Neonatal Synapse Elimination Is Delayed In Ncam Null Junctionssupporting

confidence: 53%

Structural and Functional Alterations of Neuromuscular Junctions in NCAM-Deficient Mice

2000

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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].…”

Section: Discussionmentioning

confidence: 99%

“…The idea that the survival of developing motoneurons and their synapses depends on competition for targetderived trophic factors is both pervasive and long stand ing [recent reviews : Purves, 1988;Purves et al, 1988;Betz et al, 1990;Lichtman and Balice-Gordon, 1990;Herrera and Werle, 1990;Barde, 1989;Oppenheim, 1991;Thoenen et al. 1993;Colman and Lichtman, 1993;Ip and Yancopoulos, 1994], Hamburger [1934Hamburger [ , 1939 provided an early hint that developing motoneu rons might compete for target-derived trophic factors by demonstrating that the number of surviving motoneurons is a function of target size.…”

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confidence: 99%

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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“…The nerve terminal and postsynaptic structure expand and AChRs become metabolically stable. The final stage involves the postnatal maturation of the neuromuscular junction and includes numerous changes on both a cellular and a molecular level: AChR subunits and channel kinetics change (Sakmann and Brenner, 1978;Mishina et al, 1986;Gu and Hall, 1988), synaptic vesicle proteins are restricted to the nerve terminal (Lupa and Hall, 1989;Dahm and Landmesser, 1991) subsynaptic folds appear (Terivainen, 1968;Kelly and Zacks, 1969) and polyneuronal innervation is eliminated (Betz et al, 1990).…”

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confidence: 99%

Aggregation of sodium channels during development and maturation of the neuromuscular junction

Lupa

Schaller

et al. 1993

J. Neurosci.

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The voltage-activated Na channel (NaCh) is an integral membrane protein that is enriched at the neuromuscular end plate. Using loose-patch voltage-clamp and immunofluorescence, we have found that the aggregation of NaChs occurs late, during maturation of the neuromuscular junction. A decline in expression of embryonic NaCh mRNA and increase in adult NaCh mRNA precedes the onset of aggregation, and the appearance of functional adult NaChs coincides with NaCh aggregation. We tested the possibility that only the adult NaCh subtype could aggregate during development and found that both the embryonic and adult isoforms become concentrated at the synapse. The NaCh is the first postsynaptic membrane protein shown to become clustered postnatally, and the mechanism producing this aggregation appears to be different from the process producing aggregation of other synaptic proteins.

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Competitive mechanisms underlying synapse elimination in the lumbrical muscle of the rat

Cited by 44 publications

References 36 publications

Structural and Functional Alterations of Neuromuscular Junctions in NCAM-Deficient Mice

Structural and Functional Alterations of Neuromuscular Junctions in NCAM-Deficient Mice

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

Aggregation of sodium channels during development and maturation of the neuromuscular junction

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