LRP4 SIGNALS BACK TO AXON CLUSTERING OF LRP4 AND MuSK BY AGRIN CLUSTERING OF ACETYLCHOLINE RECEPTORS Agrin Agrin axon terminal axon terminal basal lamina MuSK (Agrin co-receptor) MuSK LRP4 (Agrin receptor) LRP4acetylcholine receptor axon of motor neuron muscle fber (A) (C) (B) new synapse muscle fber Figure 21–83 Reciprocal signaling during neuromuscular synapse differentiation. (a) the agrin receptor Lrp4 and its co-receptor MuSK cluster in the muscle cell membrane in the general neighborhood of the future synapse. (B) as the growth cone approaches, it recognizes Lrp4, which stimulates differentiation of presynaptic structures. reciprocally, agrin is released from the nerve terminal, binds to a complex of Lrp4 and MuSK in the muscle, and (c) promotes the further and more focused clustering of the Lrp4 and acetylcholine receptors in the muscle cell. although the agrin/MuSK/Lrp4 machinery organizes the synapse, the process also depends on electrical signaling via the acetylcholine receptors. It is not yet known how Lrp4 signals to the motor axon.
Figure 21–82 Formation of the neuromuscular junction. (a) the growth cone of a motor axon approaches the muscle fiber. (B) Initial synapse formation is characterized by the accumulation of synaptic vesicles at the axon terminal and the formation of a specialized basal lamina in the synaptic cleft. (c) as the neuromuscular junction matures, the synaptic cleft accumulates basal lamina and extracellular matrix proteins, synaptic vesicles cluster at presynaptic release sites, and neurotransmitter receptors cluster at postsynaptic sites. Schwann (glial) cells accompany the motor axon and wrap around its terminus outside the region of synaptic contact. (D) transmission electron micrograph of the region of synaptic contact. [D, courtesy of John heuser, from J. Electron Microsc. 60 (Suppl 1), 2011. With permission from Oxford University press.]
The two-way exchange of signals between axon growth cones and muscle cells controls the initial formation of neuromuscular junctions, but it is only the first step in the establishment of the final pattern of the synaptic connections. Each muscle cell at first receives synapses from several motor neurons, but in the end it is left innervated by only one. This process of synapse elimination depends on active synaptic communication and electrical activity. If synaptic transmission is blocked by a toxin that binds to the acetylcholine receptors in the muscle cell membrane, or if axonal electrical activity is blocked by a toxin that binds to sodium channels in the axon plasma membrane, the muscle cell retains its multiple innervation beyond the normal time of elimination.
The phenomenon of activity-dependent synapse elimination is encountered in almost every part of the developing vertebrate nervous system (Figure 21–84). It has a key role, for example, in the refinement of the retinotopic map discussed earlier. Synapses are first formed in abundance and distributed over a broad target field; then the system of connections is pruned back and remodeled by competitive processes that depend on electrical activity and synaptic signaling. The elimination of synapses in this way is distinct from the elimination of surplus neurons by cell death, and it occurs after the period of normal neuronal death is over. Synapse remodeling during neural development, however, involves more than just synapse elimination; it also involves synapse reinforcement, as we discuss next.