Abstract
Author SummaryEarly in development, neurons make multiple synaptic connections with their target cells. Over time, many of these connections disappear, leaving behind a fraction of the original connections. Because this pruning occurs when mammals first leave the uterus, it's thought that this type of remodeling may serve to sculpt the nervous system to match a particular environment. However, what causes synapse elimination is not well understood. In this study, we use in vivo imaging to study the connections between motor neuron axons and their target muscle cells, at the neuromuscular junction (NMJ), during a developmental stage when each NMJ has multiple connections. We find that synapse loss is driven by competition between nerve cells vying to remain in contact with the same target cell. We show that an axon that would have been eliminated can always be spared by removing (with laser microsurgery) another axon converging on the same synaptic site. The remaining axon not only survives but rapidly grows to occupy the synaptic sites vacated by the removed axon. These results provide a framework for understanding synaptic rearrangements in the developing nervous system.
Highlights
Physiological evidence that axons completely lose connections with some postsynaptic cells as part of naturally occurring development was first observed at the neuromuscular junction in mammals more than 40 years ago [1]
We use in vivo imaging to study the connections between motor neuron axons and their target muscle cells, at the neuromuscular junction (NMJ), during a developmental stage when each NMJ has multiple connections
We find that synapse loss is driven by competition between nerve cells vying to remain in contact with the same target cell
Summary
Physiological evidence that axons completely lose connections with some postsynaptic cells as part of naturally occurring development was first observed at the neuromuscular junction in mammals more than 40 years ago [1]. Evidence for local regulation includes the following: (1) the axonal inputs that are eliminated from neuromuscular junctions do so by gradually vacating their synaptic contact sites [4] rather than suddenly undergoing degeneration, as occurs when axons are damaged [5]; (2) the axon that is maintained increases its synaptic contact area by gradually occupying many of the synaptic sites that were previously occupied by other motor axons [4]; (3) the loss and acquisition of synaptic sites is paralleled by a local reduction and strengthening in synaptic efficacy [6]; (4) the loss of axonal branches from one axon that projects to many muscle fibers occurs asynchronously, suggesting that the timing of elimination is not set by a signal from the cell soma but regulated independently at each neuromuscular junction site [7]; (5) local differences between the synaptic activity of axons converging at the same neuromuscular junction have the ability to cause synapses to be eliminated [8,9]; (6) local changes in target cell signaling can affect synapse maintenance [10]; and (7) once an axon has vacated all of its synaptic territory at a neuromuscular junction, it locally sheds cytoplasm that is internalized by glia associated with the neuromuscular junction entry zone [4,11] These data argue that the ultimate identity of the one permanent presynaptic input to a muscle fiber is determined by events occurring at the level of individual neuromuscular junctions. Other data suggest that neuronal properties (as opposed to synaptic properties) such as an axon’s biochemical identity or its firing pattern play a role in determining the outcome of synapse elimination, but even these may operate through local synaptic mechanisms [12]
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