Uptake and recycling of pro-BDNF for transmitter-induced secretion by cortical astrocytes.
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.
Department of Human and General Physiology, University of Bologna, I-40126 Bologna, Italy.
Matteo
M
Bergami
Spartaco
S
Santi
Elena
E
Formaggio
Cinzia
C
Cagnoli
Claudia
C
Verderio
Robert
R
Blum
Benedikt
B
Berninger
Michela
M
Matteoli
Marco
M
Canossa
D000818:Animals; D001253:Astrocytes / Q000166:cytology* / Q000378:metabolism* / Q000648:ultrastructure; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology*; D002966:Clathrin / Q000378:metabolism; D004705:Endocytosis; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000378:metabolism*; D011498:Protein Precursors / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D020800:Receptor, Nerve Growth Factor / Q000378:metabolism; D009435:Synaptic Transmission; D013572:Synaptic Vesicles / Q000378:metabolism; D050988:Vesicle-Associated Membrane Protein 2 / Q000378:metabolism
D019208:Brain-Derived Neurotrophic Factor; D002966:Clathrin; D018377:Neurotransmitter Agents; D011498:Protein Precursors; D020800:Receptor, Nerve Growth Factor; D050988:Vesicle-Associated Membrane Protein 2