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© The Rockefeller University Press, 0021-9525/2000/3/1295/ $5.00
The Journal of Cell Biology, Volume 148, Number 6, March 20, 2000 1295-1304

Original Article

The Tissue Plasminogen Activator (tPA)/Plasmin Extracellular Proteolytic System Regulates Seizure-induced Hippocampal Mossy Fiber Outgrowth through a Proteoglycan Substrate

Yan Ping Wua, Chia-Jen Siaoa,b, Weiquan Lua,b, Tsung-Chang Sungb, Michael A. Frohmanb, Peter Mileve, Thomas H. Bugged, Jay L. Degend, Joel M. Levinec, Richard U. Margolise, and Stella E. Tsirkaa,b
a Department of Psychiatry, University Medical Center at Stony Brook, Stony Brook, New York 11794-8651
b Department of Pharmacological Sciences, University Medical Center at Stony Brook, Stony Brook, New York 11794-8651
c Department of Neurobiology and Behavior, University Medical Center at Stony Brook, Stony Brook, New York 11794-8651
d Division of Developmental Biology, Children's Hospital Research Foundation, Cincinnati, Ohio 45229
e Department of Pharmacology, New York University Medical Center, New York, New York 10016

Correspondence to: Stella E. Tsirka, Department of Psychiatry, HSC, T10, Room 046, University Medical Center at Stony Brook, Stony Brook, NY 11794-8101. Tel:631-444-3859 Fax:631-444-7534 E-mail:stsirka{at}mail.psychiatry.sunysb.edu.

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.

Key Words: neurite, dentate, nonproteolytic, kainic acid, seizure


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