Neuronal depolarization enhances the transcription of the neuronal serine protease inhibitor neuroserpin

Neuroserpin is an axonally secreted neuronal serine protease inhibitor. Bas ed on its inhibitory activity towards tissue plasminogen activator (tPA) an d its predominant expression in the cerebral cortex, the hippocampus, and t he amygdala, a role for neuroserpin in the regulation of neural plasticity has been suggested. We recently found that neuroserpin mRNA is increased in cultured hippocampal neurons upon depolarization with elevated extracellul ar KCI. Using luciferase reporter constructs containing segments of the pro moter region of the neuroserpin gene, we identified a 200-bp segment near t he transcription initiation site that is responsible for both the neuron-sp ecific expression of the neuroserpin gene and the enhanced transcription re sulting from depolarization. Nerve growth factor, which alone had no effect on the expression of neuroserpin mRNA in hippocampal neurons, had a marked potentiating effect when supplied in combination with elevated extracellul ar KCl. In contrast, the transcription factor zif/268 blocked neuroserpin t ranscription. These results implicate neuroserpin as an activity-regulated modulator of tPA activity at the synapse and provide further support for th e occurrence of activity-regulated proteolytic processes at the synapse.