Modulation of neuronal plasticity by extracellular serine proteases and their inhibitors : proteolytic control of NMDA receptors

Serine proteases are enzymes catalyzing protein cleavage. Because of their capability to cleave a wide variety of substrates, they are involved in many critical physiological processes such as digestion, hemostasis, reproduction and immune response, as well as in developmental processes, signal transduction and apoptosis. In the last years, there is also increasing evidence for their role in the control of plasticity-related events in the adult and developing central nervous system, and involvement in phenomena such as memory and learning. Protease nexin-1 (PN-1) is a 43 kDa glycoprotein belonging to the serpin superfamily. It strongly inhibits the activity of several serine proteases such as thrombin, tissue plasminogen activator (tPA), urokinase plasminogen activator (uPA), trypsin and plasmin. PN-1 has a complex spatial and temporal expression pattern in the adult and developing nervous system, and its expression is enhanced upon CNS lesions. Mice lacking PN-1 have reduced long-term potentiation (LTP) in the hippocampus, and are more prone to seizures, while mice overexpressing it develop a progressive neurodegenerative disorder. These findings suggest a role for PN-1 in brain function and homeostasis. In this thesis the role of PN-1 in adult brain plasticity was examined. Activitydependent expression of PN-1 was demonstrated using an in vivo reporter system. PN-1 was found to be crucial for the control of brain proteolytic activity, and PN-1-/mice displayed decreased levels of the NR1 subunit of the N-methyl-D-aspartate (NMDA) receptor in the cortex and hippocampus. Electrophysiological examination of adult PN-1-/- mice revealed decreased NMDA receptor signaling in the barrel cortex, and decreased sensory evoked potentials upon whisker stimulation. Behavioral tests showed that PN-1-/- mice also displayed impaired whisker-dependent sensory motor function. Thus, a tight control of serine protease activity was shown to be critical for the in vivo function of NMDA receptors, and the proper function of sensory pathways.