The tissue plasminogen activator (tPA)/plasmin extracellular proteolytic system regulates seizure-induced hippocampal mossy fiber outgrowth through a proteoglycan substrate.
Short seizure episodes are associated with remodeling of neuronal connections. One region where such reorganization occurs is the hippocampus, and in particular, the mossy fiber pathway. Using genetic and pharmacological approaches, we show here a critical role in vivo for tissue plasminogen activator (tPA), an extracellular protease that converts plasminogen to plasmin, to induce mossy fiber sprouting. We identify DSD-1-PG/phosphacan, an extracellular matrix component associated with neurite reorganization, as a physiological target of plasmin. Mice lacking tPA displayed decreased mossy fiber outgrowth and an aberrant band at the border of the supragranular region of the dentate gyrus that coincides with the deposition of unprocessed DSD-1-PG/phosphacan and excessive Timm-positive, mossy fiber termini. Plasminogen-deficient mice also exhibit the laminar band and DSD- 1-PG/phosphacan deposition, but mossy fiber outgrowth through the supragranular region is normal. These results demonstrate that tPA functions acutely, both through and independently of plasmin, to mediate mossy fiber reorganization.
Wu
Y P
YP
Department of Psychiatry, University Medical Center at Stony Brook, Stony Brook, New York 11794-8651, USA.
Siao
C J
CJ
Lu
W
W
Sung
T C
TC
Frohman
M A
MA
Milev
P
P
Bugge
T H
TH
Degen
J L
JL
Levine
J M
JM
Margolis
R U
RU
Tsirka
S E
SE
D000679:Amygdala / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology; D000818:Animals; D011508:Chondroitin Sulfate Proteoglycans / Q000502:physiology*; D005341:Fibrinolysin / Q000378:metabolism*; D006624:Hippocampus / Q000502:physiology* / Q000503:physiopathology / Q000648:ultrastructure; D007608:Kainic Acid / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009412:Nerve Fibers / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D016501:Neurites / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D010958:Plasminogen / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5; D012640:Seizures / Q000139:chemically induced / Q000503:physiopathology*; D010959:Tissue Plasminogen Activator / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D011508:Chondroitin Sulfate Proteoglycans; D010958:Plasminogen; C516896:Ptprz1 protein, mouse; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin; D007608:Kainic Acid