71 Molecular interactions that facilitate the growth of commissural axons across the midline

The postnatal reduction in an initially redundant polyneuronal innervation of skeletal muscle is dependent on neuromuscular activity. We have shown that the activity-dependent synapse reduction (ADSR) ts robustly expressed in a tissue culture system. The degree to which the loss is selective for the inactive inputs to the muscle apprears to be related to the amount of stimulation delivered to the preparations. The ADSR can be completely blocked by nanomolar concentrations of hirudin (a specific thrombin inhibitor) and protease nexin 1 (PNI), an endogenous serine protease inhibitor. Exogenous thrombin produces synapse loss in quiescent preparations and this loss is prevented by hirudin. Cholinergic stimulation of cultured mouse my&t&s increases secretion of thrombin activity and levels of prothrombin mRNA in the muscle cells. PNl message levels are little, if any, changed by cholinergic stimulation. Neuronal survival in CNS cultures can be influenced by thrombin (iucreased cell death) or PNI (mcre.ased cell survival). We conclude that in both peripheral and central synaptic systems, a balanced expression of thrombiu or thrombin-like proteases and their inhibitors is critically involved in ADSR and neuronal survival and thus in the developing architecture of synaptic circuits.