Activity-dependent BDNF release via endocytic pathways is regulated by synaptotagmin-6 and complexin

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 112; no. 32; pp. E4475 - E4484
• Main Authors: Wong, Yu-Hui, Lee, Chia-Ming, Xie, Wenjun, Cui, Bianxiao, Poo, Mu-ming
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 11.08.2015; National Acad Sciences
• Series: PNAS Plus
• Subjects: Adaptor Proteins, Vesicular Transport - metabolism; Animals; Axons - metabolism; Biological Sciences; Brain-Derived Neurotrophic Factor - metabolism; Calcium - metabolism; Cell Compartmentation; Cells, Cultured; Dendrites; Down-Regulation; Endocytosis; Exocytosis; Gene Knockdown Techniques; Green Fluorescent Proteins - metabolism; Hippocampus - cytology; Intracellular Space - metabolism; Membranes; Mice; Models, Biological; Molecules; Nerve Tissue Proteins - metabolism; Neurons; PNAS Plus; Protein Transport; Quantum dots; Quantum Dots - metabolism; Receptors, Glutamate - metabolism; Synapses; Synaptotagmins - metabolism; endocytosis; secretion; synaptotagmin; complexin; BDNF
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1511830112

Brain-derived neurotrophic factor (BDNF) is known to modulate synapse development and plasticity, but the source of synaptic BDNF and molecular mechanisms regulating BDNF release remain unclear. Using exogenous BDNF tagged with quantum dots (BDNF-QDs), we found that endocytosed BDNF-QDs were preferentially localized to postsynaptic sites in the dendrite of cultured hippocampal neurons. Repetitive neuronal spiking induced the release of BDNF-QDs at these sites, and this process required activation of glutamate receptors. Down-regulating complexin 1/2 (Cpx1/2) expression eliminated activity-induced BDNF-QD secretion, although the overall activity-independent secretion was elevated. Among eight synaptotagmin (Syt) isoforms examined, down-regulation of only Syt6 impaired activity-induced BDNF-QD secretion. In contrast, activity-induced release of endogenously synthesized BDNF did not depend on Syt6. Thus, neuronal activity could trigger the release of endosomal BDNF from postsynaptic dendrites in a Cpxand Syt6-dependent manner, and endosomes containing BDNF may serve as a source of BDNF for activity-dependent synaptic modulation.