Coincident pre- and postsynaptic activation induces dendritic filopodia via neurotrypsin-dependent agrin cleavage.
The synaptic serine protease neurotrypsin is essential for cognitive function, as its deficiency in humans results in severe mental retardation. Recently, we demonstrated the activity-dependent release of neurotrypsin from presynaptic terminals and proteolytical cleavage of agrin at the synapse. Here we show that the activity-dependent formation of dendritic filopodia is abolished in hippocampal neurons from neurotrypsin-deficient mice. Administration of the neurotrypsin-dependent 22 kDa fragment of agrin rescues the filopodial response. Detailed analyses indicated that presynaptic action potential firing is necessary for the release of neurotrypsin, whereas postsynaptic NMDA receptor activation is necessary for the neurotrypsin-dependent cleavage of agrin. This contingency characterizes the neurotrypsin-agrin system as a coincidence detector of pre- and postsynaptic activation. As the resulting dendritic filopodia are thought to represent precursors of synapses, the neurotrypsin-dependent cleavage of agrin at the synapse may be instrumental for a Hebbian organization and remodeling of synaptic circuits in the CNS.
Matsumoto-Miyai
Kazumasa
K
Department of Biochemistry, University of Zurich, Zurich, Switzerland.
Sokolowska
Ewa
E
Zurlinden
Andreas
A
Gee
Christine E
CE
Lüscher
Daniel
D
Hettwer
Stefan
S
Wölfel
Jens
J
Ladner
Ana Paula
AP
Ster
Jeanne
J
Gerber
Urs
U
Rülicke
Thomas
T
Kunz
Beat
B
Sonderegger
Peter
P
D018171:Agrin / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D003712:Dendrites / Q000378:metabolism*; D005089:Exocytosis; D006624:Hippocampus / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008822:Mice, Transgenic; D016296:Mutagenesis; D017729:Presynaptic Terminals; D011554:Pseudopodia / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*
D018171:Agrin; D012697:Serine Endopeptidases; C108493:neurotrypsin