Schwann cells participate in synapse elimination at the developing neuromuscular junction

Abstract

During the initial stages of innervation of developing skeletal muscles, the terminal branches of axons from multiple motor neurons form neuromuscular junctions (NMJs) on a small region of each muscle fiber, the motor endplate. Subsequently, the number of axonal inputs at the endplate region is reduced so that, at maturity, each muscle fiber is innervated by the terminals of a single motor neuron. The Schwann cells associated with the axon terminals are involved in the removal of these synapses but do not select the axon that is ultimately retained on each fiber. Schwann cells perform this function by disconnecting terminal branches from the myofiber surface and by attacking them phagocytically. Here we discuss how this behavior is regulated and argue that such regulation is not unique to development of neuromuscular innervation but is also expressed in the response of the mature NMJ to various manipulations and pathologies.

Figure 1. The arrangement of the cellular components at mouse neuromuscular junction

(A) At mature NMJs, each tSCs (shown in shades of green) covers a non-overlapping portion of the nerve terminal (blue) that in turn covers the postsynaptic AChRs (indicated in red). At neonatal NMJs, this partitioning of terminals by tSCs has not yet been established and these cells interdigitate. Processes of the neonatal tSCs (in shades of green) make synapse-like apposition to the portions of the postsynaptic AChR aggregates unoccupied by the immature nerve terminals (in shades of blue). (B) Confocal images of the postsynaptic AChR aggregate (AChR), the motor axon terminals (nerve) and Schwann cells (SC) at a neonatal NMJ. As illustrated in (A), a significant portion of the oval-shaped AChR aggregate is not apposed by the innervating motor axon terminals, but rather by the processes of tSCs. (B) Electron micrograph of a single section in a serial series showing a tSCs consuming a portion of the presynaptic motor axon terminal (NT) that is still in contact with the target muscle fiber (M). A phagocytic vesicle containing components of the nerve terminal (arrowhead) is situated within tSC cytoplasm and has almost completely pinched off (double arrowhead) from this nerve terminal. Scale bars: 10 μm in (B) and 500 nm in (C).

Figure 2. Changes to morphology of adult NMJs in response to NRG1-III overexpression by motor neurons

Unlike the mature NMJs of control mice, those in animals that overexpress NRG1-III show signs of remodeling. The postsynaptic AChR aggregates are no longer found in “pretzel-like” continuous gutters, but in fragmented islands that are innervated by varicose presynaptic terminal branches. Some AChR-islands are abandoned by the motor terminal branches (arrowhead) and appear to be in the process of elimination. In addition, there is a significant increase in the number of tSCs, some of which extend long processes within and beyond the synaptic area. Scale bar: 10 μm.