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The Journal of Neuroscience, February 13, 2008, 28(7):1568-1579; doi:10.1523/JNEUROSCI.3398-07.2008
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Cellular/Molecular
Activity-Induced Synaptic Capture and Exocytosis of the Neuronal Serine Protease Neurotrypsin
Renato Frischknecht,1,2 * Anna Fejtova,1,2 * Miriam Viesti,1 Alexander Stephan,1 andPeter Sonderegger1 1Department of Biochemistry, University of Zurich, CH-8057 Zurich, Switzerland, and 2Department of Neurochemistry, Leibniz Institute of Neurobiology, D-39118 Magdeburg, Germany
Correspondence should be addressed to Dr. Peter Sonderegger, Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland. Email: peter.sonderegger{at}bioc.uzh.ch
Extracellular proteolysis plays an essential role in synaptic remodeling that is indispensable for cognitive function. The extracellular serine protease neurotrypsin was implicated in cognitive function, because humans lacking a functional form of neurotrypsin suffer from severe mental retardation. By immunoelectron microscopy, neurotrypsin has been localized to presynaptic terminals, suggesting a local proteolytic function after its synaptic release. Here, we studied axonal trafficking and synaptic exocytosis of neurotrypsin by live imaging of hippocampal neurons expressing neurotrypsin fused with enhanced green fluorescent protein or its pH-sensitive variant, superecliptic pHluorin. In differentiated neurons, we identified neurotrypsin in mobile transport vesicles along axons and in both an intracellular and an extracellular pool at synapses. Short depolarization triggered rapid synaptic exocytosis of neurotrypsin. Once externalized, neurotrypsin lingered at its synaptic release site for several minutes before it disappeared. Cell depolarization also enhanced synaptic capture of intracellular neurotrypsin transport vesicles, and elevated synaptic activity increased both number and motility of mobile axonal neurotrypsin vesicles. We further observed trading of neurotrypsin vesicles between adjacent synapses. These activities may support the replenishment of neurotrypsin after activity-induced synaptic exocytosis. Together, the activity-dependent recruitment of neurotrypsin to synapses and its exocytosis and transient persistence at its synaptic release site argue for a spatially and temporally restricted proteolytic action at the synapse. Thereby, neurotrypsin may play a role in activity-dependent remodeling of the synaptic circuitry that is key to adaptive synaptic changes in the context of cognitive functions, such as learning and memory.
Key words: extracellular proteolysis; mental retardation; cognitive function; synaptic plasticity; activity-dependent secretion; synaptic capture
Received July 26, 2007; revised Nov. 28, 2007; accepted Dec. 18, 2007.
Correspondence should be addressed to Dr. Peter Sonderegger, Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland. Email: peter.sonderegger{at}bioc.uzh.ch
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