The possibility that plasminogen activator (PA) plays a role in synaptic plasticity was explored in the spinal cord during the crossed phrenic phenomenon (CPP), where respiratory functional plasticity develops following spinal cord injury. Synaptic remodeling on phrenic motorneurons occurs during the characteristic delay period following spinal cord injury before CPP recovery of respiratory function. The molecular mechanisms underlying this plasticity are not well-defined. During the critical 1-2 h delay period required for this synaptic plasticity following a C2 hemisection in mice, uPA and tPA mRNAs are rapidly induced in C4-5 ventral spinal cord neurons in the ipsilateral phrenic motor nucleus (PMN), as are uPA and tPA protein levels. A role for uPA in CPP spinal cord plasticity is confirmed by the impaired ability of uPA knockout mice to acquire a good CPP response by 6 h post-hemisection and their lack of structural remodeling of PMN synapses that underlies development of the CPP response.