title: Activity-dependent BDNF release via endocytic pathways is regulated by synaptotagmin-6 and complexin.
abstract: 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 Cpx- and Syt6-dependent manner, and endosomes containing BDNF may serve as a source of BDNF for activity-dependent synaptic modulation.
authors.affiliation: Division of Neurobiology, Department of Molecular and Cell Biology, Helen Wills Neuroscience Institute, University of California, Berkeley, CA 94720;
authors.forename: Yu-Hui
authors.initials: YH
authors.lastname: Wong
authors.affiliation: Division of Neurobiology, Department of Molecular and Cell Biology, Helen Wills Neuroscience Institute, University of California, Berkeley, CA 94720;
authors.forename: Chia-Ming
authors.initials: CM
authors.lastname: Lee
authors.affiliation: Department of Chemistry, Stanford University, Stanford, CA 94305;
authors.forename: Wenjun
authors.initials: W
authors.lastname: Xie
authors.affiliation: Department of Chemistry, Stanford University, Stanford, CA 94305;
authors.forename: Bianxiao
authors.initials: B
authors.lastname: Cui
authors.affiliation: Division of Neurobiology, Department of Molecular and Cell Biology, Helen Wills Neuroscience Institute, University of California, Berkeley, CA 94720; Institute of Neuroscience, State Key Laboratory of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China mpoo@berkeley.edu.
authors.forename: Mu-ming
authors.initials: MM
authors.lastname: Poo
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism*; D000818:Animals; D001369:Axons / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002451:Cell Compartmentation; D002478:Cells, Cultured; D003712:Dendrites; D015536:Down-Regulation; D004705:Endocytosis; D005089:Exocytosis; D055785:Gene Knockdown Techniques; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology; D042541:Intracellular Space / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D021381:Protein Transport; D045663:Quantum Dots / Q000378:metabolism; D017470:Receptors, Glutamate / Q000378:metabolism; D013569:Synapses; D050857:Synaptotagmins / Q000378:metabolism*
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D019208:Brain-Derived Neurotrophic Factor; D009419:Nerve Tissue Proteins; D017470:Receptors, Glutamate; C095992:complexin I; C485184:enhanced green fluorescent protein; D050857:Synaptotagmins; D049452:Green Fluorescent Proteins; D002118:Calcium
keywords: BDNF; complexin; endocytosis; secretion; synaptotagmin