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Science 306 (5695): 487-491

Copyright © 2004 by the American Association for the Advancement of Science

Cleavage of proBDNF by tPA/Plasmin Is Essential for Long-Term Hippocampal Plasticity

Petti T. Pang,1,3 Henry K. Teng,2 Eugene Zaitsev,1 Newton T. Woo,1 Kazuko Sakata,1 Shushuang Zhen,2 Kenneth K. Teng,2 Wing-Ho Yung,3 Barbara L. Hempstead,2 Bai Lu1*

Abstract: Long-term memory is thought to be mediated by protein synthesis–dependent, late-phase long-term potentiation (L-LTP). Two secretory proteins, tissue plasminogen activator (tPA) and brain-derived neurotrophic factor (BDNF), have been implicated in this process, but their relationship is unclear. Here we report that tPA, by activating the extracellular protease plasmin, converts the precursor proBDNF to the mature BDNF (mBDNF), and that such conversion is critical for L-LTP expression in mouse hippocampus. Moreover, application of mBDNF is sufficient to rescue L-LTP when protein synthesis is inhibited, which suggests that mBDNF is a key protein synthesis product for L-LTP expression.

1 Section on Neural Development and Plasticity, Laboratory of Cellular and Synaptic Neurophysiology, National Institute of Child Health and Human Development (NICHD), Bethesda, MD 20892, USA.
2 Division of Hematology, Department of Medicine, Weill Medical College of Cornell University, New York, NY 10021, USA.
3 Department of Physiology, Faculty of Medicine, Chinese University of Hong Kong, Shatin, New Territories, Hong Kong.

* To whom correspondence should be addressed. E-mail: bailu{at}mail.nih.gov


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J. Mojsilovic-Petrovic, G.-B. Jeong, A. Crocker, A. Arneja, S. David, D. Russell, and R. G. Kalb (2006)
J. Neurosci. 26, 9250-9263
   Abstract »    Full Text »    PDF »
The many faces of amnesia..
P. E. Gold (2006)
Learn. Mem. 13, 506-514
   Abstract »    Full Text »    PDF »
Neural stem cells rescue nervous purkinje neurons by restoring molecular homeostasis of tissue plasminogen activator and downstream targets..
J. Li, J. Imitola, E. Y. Snyder, and R. L. Sidman (2006)
J. Neurosci. 26, 7839-7848
   Abstract »    Full Text »    PDF »
Current advances in local protein synthesis and synaptic plasticity..
B. E. Pfeiffer and K. M. Huber (2006)
J. Neurosci. 26, 7147-7150
   Abstract »    Full Text »    PDF »
Analysis of Knock-Out Mice to Determine the Role of HPC-1/Syntaxin 1A in Expressing Synaptic Plasticity.
T. Fujiwara, T. Mishima, T. Kofuji, T. Chiba, K. Tanaka, A. Yamamoto, and K. Akagawa (2006)
J. Neurosci. 26, 5767-5776
   Abstract »    Full Text »    PDF »
Purkinje neuron degeneration in nervous (nr) mutant mice is mediated by a metabolic pathway involving excess tissue plasminogen activator.
J. Li, Y. Ma, Y. D. Teng, K. Zheng, T. K. Vartanian, E. Y. Snyder, and R. L. Sidman (2006)
PNAS 103, 7847-7852
   Abstract »    Full Text »    PDF »
Activity-dependent release of precursor nerve growth factor, conversion to mature nerve growth factor, and its degradation by a protease cascade.
M. A. Bruno and A. C. Cuello (2006)
PNAS 103, 6735-6740
   Abstract »    Full Text »    PDF »
Matrix Metalloproteinase-9 Is Required for Hippocampal Late-Phase Long-Term Potentiation and Memory.
V. Nagy, O. Bozdagi, A. Matynia, M. Balcerzyk, P. Okulski, J. Dzwonek, R. M. Costa, A. J. Silva, L. Kaczmarek, and G. W. Huntley (2006)
J. Neurosci. 26, 1923-1934
   Abstract »    Full Text »    PDF »
Differential Gender-Related Vulnerability to Depression Induction and Converging Antidepressant Responses in Rats.
M.-K. Sun and D. L. Alkon (2006)
J. Pharmacol. Exp. Ther. 316, 926-932
   Abstract »    Full Text »    PDF »
Two Signaling Pathways Regulate the Expression and Secretion of a Neuropeptide Required for Long-Term Facilitation in Aplysia.
J.-Y. Hu, F. Wu, and S. Schacher (2006)
J. Neurosci. 26, 1026-1035
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Tissue plasminogen activator and plasminogen mediate stress-induced decline of neuronal and cognitive functions in the mouse hippocampus.
R. Pawlak, B. S. S. Rao, J. P. Melchor, S. Chattarji, B. McEwen, and S. Strickland (2005)
PNAS 102, 18201-18206
   Abstract »    Full Text »    PDF »
Crystal Structure of Kunitz Domain 1 (KD1) of Tissue Factor Pathway Inhibitor-2 in Complex with Trypsin: IMPLICATIONS FOR KD1 SPECIFICITY OF INHIBITION.
A. E. Schmidt, H. S. Chand, D. Cascio, W. Kisiel, and S. P. Bajaj (2005)
J. Biol. Chem. 280, 27832-27838
   Abstract »    Full Text »    PDF »
Vertebrate GLD2 poly(A) polymerases in the germline and the brain.
L. ROUHANA, L. WANG, N. BUTER, J. E. KWAK, C. A. SCHILTZ, T. GONZALEZ, A. E. KELLEY, C. F. LANDRY, and M. WICKENS (2005)
RNA 11, 1117-1130
   Abstract »    Full Text »    PDF »
Sortilin Controls Intracellular Sorting of Brain-Derived Neurotrophic Factor to the Regulated Secretory Pathway.
Z.-Y. Chen, A. Ieraci, H. Teng, H. Dall, C.-X. Meng, D. G. Herrera, A. Nykjaer, B. L. Hempstead, and F. S. Lee (2005)
J. Neurosci. 25, 6156-6166
   Abstract »    Full Text »    PDF »
ProBDNF Induces Neuronal Apoptosis via Activation of a Receptor Complex of p75NTR and Sortilin.
H. K. Teng, K. K. Teng, R. Lee, S. Wright, S. Tevar, R. D. Almeida, P. Kermani, R. Torkin, Z.-Y. Chen, F. S. Lee, et al. (2005)
J. Neurosci. 25, 5455-5463
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The neurotrophin receptor p75NTR modulates long-term depression and regulates the expression of AMPA receptor subunits in the hippocampus.
H. Rosch, R. Schweigreiter, T. Bonhoeffer, Y.-A. Barde, and M. Korte (2005)
PNAS 102, 7362-7367
   Abstract »    Full Text »    PDF »
Persistent Phosphorylation by Protein Kinase M{zeta} Maintains Late-Phase Long-Term Potentiation.
P. Serrano, Y. Yao, and T. C. Sacktor (2005)
J. Neurosci. 25, 1979-1984
   Abstract »    Full Text »    PDF »

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