Activity-dependent elimination of neuromuscular synapses

Abstract

At developing neuromuscular synapses in vertebrates, different motor axon inputs to muscle fibers compete for maintenance of their synapses. Competition results in progressive changes in synaptic structure and strength that lead to the weakening and loss of some inputs, a process that has been called synapse elimination. At the same time, a single input is strengthened and maintained throughout adult life, consistently recruiting muscle fibers to contract even at rapid firing rates. Work over the last decade has led to an understanding of some of the cell biological mechanisms that underlie competition and how these culminate in synapse elimination. We discuss current ideas about how activity modulates neuromuscular synaptic competition, how competition leads to synapse loss, and how these processes are modulated by cell-cell signaling. A common feature of competition at neuromuscular as well as CNS synapses is that temporally correlated activity seems to slow or prevent competition, while uncorrelated activity seems to trigger or enhance competition. Important questions that remain to be addressed include how patterns of motor neuron activity affect synaptic strength, what is the temporal relationship between changes in synaptic strength and structure, and what cellular signals mediate synapse loss. Answers to these questions will expand our understanding of the mechanisms by which activity edits synaptic structure and function, writing permanent changes in neural circuitry.

Role of pro-brain-derived neurotrophic factor (proBDNF) to mature BDNF conversion in activity-dependent competition at developing neuromuscular synapses

“…Extensive experimental data support the view that the more active terminal or "cartel" gets stabilized, whereas less active ones withdraw, resulting in canonical elimination of polyneuronal innervation (8,11). It is generally believed that this synaptic competition is mediated by a "punishment" or "elimination" signal, produced by the postsynaptic cell, that causes the retraction of the inactive terminals, as well as a "protective" or "reward" signal that stabilizes the active terminal (10)(11)(12). Despite significant efforts over decades, the identity of the punishment or reward signals remains unknown (4,13).…”

“…Activitydependent synaptic competition, a general process seen in many parts of the developing nervous system, plays a critical role in shaping patterns of neuronal connections (2)(3)(4)(5)(6)(7). At the neuromuscular junction (NMJ), for example, multiple axons compete for the same postsynaptic muscle cell during early postnatal life until all but one is eliminated (8)(9)(10). Extensive experimental data support the view that the more active terminal or "cartel" gets stabilized, whereas less active ones withdraw, resulting in canonical elimination of polyneuronal innervation (8,11).…”

Role for the skeletal muscle action potential in non‐Hebbian long‐term depression at the amphibian (Bufo marinus) neuromuscular junction

“…However, stable polyneuronal innervation of mature neuromuscular junctions is well-supported in amphibia, where two (or sometimes more) axons form synaptic connections that are distributed along the long axis of a single muscle fiber (Lateva et al, 2002). More recently, multiple endplates, subserved by different motoneurons (Duxson and Sheard, 1995;Happak et al, 1997;Zenker et al, 1990) and separated by up to 46 mm, have been identified on mature muscles in a variety of species (Wyatt and Balice-Gordon, 2003).…”

“…This can be seen during development and re-innervation of muscle when individual fibers receive transient innervation from two or more motoneurons (Wyatt and Balice-Gordon, 2003). Differences emerge in the strength of convergent inputs during the subsequent loss of the polyneuronal innervation of the muscle cell, and a role for activity-dependent retrograde modulation of synaptic strength in this process has been postulated (Colman et al, 1997;Kopp et al, 2000).…”

Schwann Cell-Derived Factors Modulate Synaptic Activities at Developing Neuromuscular Synapses

“…The suprathreshold excitation may produce global influence in the maturation of muscle fibers (Kidokoro and Saito, 1988) as well as acetylcholine receptor distribution during synaptogenesis (Kummer et al, 2006). Furthermore, synaptic activity plays a crucial role in the transition from multiple innervation to single innervation at developing neuromuscular synapses (Wyatt and Balice-Gordon, 2003). In addition to the global effects exerted by suprathreshold spontaneous synaptic activities, recent studies suggest that spontaneous miniature synaptic transmission, independent of evoked transmitter release, may regulate local postsynaptic protein synthesis and stabilize the structure and function of developing synapses (McKinney et al, 1999;Saitoe et al, 2001;Chung and Kavalali, 2006;Sutton et al, 2006).…”