Neurotrophins regulate agrin-induced postsynaptic differentiation

The precise orchestration of synaptic differentiation is critical for effic ient information exchange in the nervous system. The nerve-muscle synapse f orms in response to agrin, which is secreted from the motor nerve terminal and induces the clustering of acetylcholine receptors (AChRs) and other ele ments of the postsynaptic apparatus on the subjacent muscle cell surface. I n view of the highly restricted spatial localization and the plasticity of neuromuscular junctions, it seems likely that synapse formation and mainten ance are regulated by additional, as-yet-unidentified factors. Here, we tes ted whether neurotrophins modulate the agrin-induced differentiation of pos tsynaptic specializations. We show that both brain-derived neurotrophic fac tor (BDNF) and neurotrophin-4 (NT-4) inhibit agrin-induced AChR clustering on cultured myotubes. Nerve growth factor and NT-3 are without effect. Musc le cells express full-length TrkB, the cognate receptor for BDNF and NT-4. Direct activation of this receptor by anti-TrkB antibodies mimicked the BDN F/NT-4 inhibition of agrin-induced AChR clustering. This BDNF/NT-4 inhibiti on is likely to be an intrinsic mechanism for regulating AChR clustering be cause neutralization of endogenous TrkB ligands resulted in elevated levels of AChR clustering even in the absence of added agrin. Finally, high conce ntrations of agrin can occlude the BDNF/NT-4 inhibition of AChR clustering. These results indicate that an interplay between agrin and neurotrophins c an regulate the formation of postsynaptic specializations. They also sugges t a mechanism for the suppression of postsynaptic specializations at nonjun ctional regions.