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Published online October 13, 2008
doi:10.1083/jcb.200806137
The Journal of Cell Biology, Vol. 183, No. 2, 213-221
The Rockefeller University Press, 0021-9525 $30.00
© 2008 Bergami et al.
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Uptake and recycling of pro-BDNF for transmitter-induced secretion by cortical astrocytes



Matteo Bergami1, Spartaco Santi3, Elena Formaggio4, Cinzia Cagnoli5, Claudia Verderio5, Robert Blum6, Benedikt Berninger7, Michela Matteoli5,8, and Marco Canossa2,9

1 Department of Human and General Physiology and 2 Department of Pharmacology, University of Bologna, I-40126 Bologna, Italy
3 Istituto di Genetica Molecolare del Consiglio Nazionale delle Ricerche e Istituti Ortopedici Rizzoli, I-40136 Bologna, Italy
4 Department of Medicine and Public Health, University of Verona, I-37134 Verona, Italy
5 Dipartimento di Farmacologia, Istituto di Neuroscienze del Consiglio Nazionale delle Ricerche, Università di Milano, I-20129 Milano, Italy
6 Department of Physiological Genomics, Institute of Physiology, Ludwig-Maximilians University Munich, D-80336 Munich, Germany
7 Institute of Stem Cell Research, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health, D-85764 Neuherberg, Germany
8 Istituto di Ricovero e Cura a Carattere Scientifico Don Gnocchi, I-20148 Milano, Italy
9 Italian Institute of Technology, I-16163 Genoa, Italy

Correspondence to Marco Canossa: marco.canossa{at}unibo.it

Activity-dependent secretion of brain-derived neurotrophic factor (BDNF) is thought to enhance synaptic plasticity, but the mechanisms controlling extracellular availability and clearance of secreted BDNF are poorly understood. We show that BDNF is secreted in its precursor form (pro-BDNF) and is then cleared from the extracellular space through rapid uptake by nearby astrocytes after {theta}-burst stimulation in layer II/III of cortical slices, a paradigm resulting in long-term potentiation of synaptic transmission. Internalization of pro-BDNF occurs via the formation of a complex with the pan-neurotrophin receptor p75 and subsequent clathrin-dependent endocytosis. Fluorescence-tagged pro-BDNF and real-time total internal reflection fluorescence microscopy in cultured astrocytes is used to monitor single endocytic vesicles in response to the neurotransmitter glutamate. We find that endocytosed pro-BDNF is routed into a fast recycling pathway for subsequent soluble NSF attachment protein receptor–dependent secretion. Thus, astrocytes contain an endocytic compartment competent for pro-BDNF recycling, suggesting a specialized form of bidirectional communication between neurons and glia.

M. Bergami and S. Santi contributed equally to this paper.

Abbreviations used in this paper: BDNF, brain-derived neurotrophic factor; GFAP, glial fibrillary acidic protein; Map2, microtubule-associated protein 2; MDC, monodansylcadaverine; QD, quantum dot; TBS, {theta}-burst stimulation; TeNT, tetanus neurotoxin; TIRF, total internal reflection fluorescence; TrkB, tropomyosin-related kinase B receptor; TrkB-t, truncated TrkB; Vamp2, vesicle-associated membrane protein 2.

© 2008 Bergami et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jcb.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).


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