Our working hypothesis is that synaptic remodeling at the neuromuscular junction is an active process that ensures proper matching between presynaptic activity and postsynaptic response under varying conditions. In this study we specifically hypothesize that this synaptic remodeling requires TrkB signaling at the presynaptic terminal. TrkB signaling requires the presence of the full length receptor (TrkB.FL) and is dependent on phosphorylation and activation of a tyrosine kinase. Using laser capture microdissection coupled with quantitative RT-PCR and protein analyses, we found that TrkB.FL is present only in phrenic motoneurons, but not in diaphragm muscle fibers. Using a specific siRNA we knocked down TrkB expression in phrenic motoneurons and found impairment of neuromuscular transmission that was associated with altered presynaptic remodeling. Using mice expressing knockin alleles that allow selective inhibition (via 1NMPP1 treatment) of Trk kinase activity (TrKBF616A) we also demonstrated impaired neuromuscular transmission and altered presynaptic remodeling. In both cases, the impairment in presynaptic remodeling involved apparent retraction of axon terminals with accumulation of neurofilament. These changes in presynaptic terminals occurred in the absence of any alterations in muscle structure or contractile function. Using a-bungarotoxin to identify postsynaptic cholinergic receptors, there was no apparent change in end-plate area or cholinergic receptor density after 2 weeks. However, previously we did observe changes in postsynaptic ultrastructure including reduced gutter depth and branching complexity which may be attributed to presynaptic effects. Together, these results support the role of endogenous TrkB signaling in neuromuscular junction remodeling.