UC San Diego

Synaptic specialization requires interactions between presynaptic postsynaptic, and glial partners. The development of mouse neuromuscular junctions is pre- patterned within a narrow central band of muscle, where motor axons undergo two aspects of presynaptic differentiation: regulated branching and specialization of nerve terminals. Evidence suggests that acetylcholine (ACh) inhibits nerve branching and presynaptic specialization, yet it is unclear whether the inhibition is mediated through postsynaptic or non-postsynaptic AChRs. Postsynaptic AChRs may play a role in pre- patterning the synapses and in eliciting a retrograde signal to induce presynaptic specialization. Here we have used genetic methods to address these issues. We report that clustering of postsynaptic AChRs is absent in muscle AChRa1 mutant mice. Like mice deficient in ACh biosynthesis, presynaptic axons are highly branched with synaptic sites distributed in a broader muscle territory, suggesting that postsynaptic AChRs are involved in pre- patterning synapses and mediates ACh inhibition of nerve branching. Surprisingly, presynaptic specialization is present in the absence of postsynaptic AChR clusters. Additional evidence supports that ACh inhibits specialization of nerve terminals through non-postsynaptic AChRs. These results suggest that ACh negatively regulates these two aspects of presynaptic differentiation via distinct mechanisms. Also presented here, through data obtained from mice that lack Schwann cells due to a loss of erbB2, are preliminary evidence for a possible role of Schwann cells in the timing of presynaptic development, in part of an ongoing project to determine the role of Schwann cells in NMJ development