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Autocrine BDNF-TrkB signalling within a single dendritic spine.

TitleAutocrine BDNF-TrkB signalling within a single dendritic spine.
Publication TypeJournal Article
Year of Publication2016
AuthorsHarward SC, Hedrick NG, Hall CE, Parra-Bueno P, Milner TA, Pan E, Laviv T, Hempstead BL, Yasuda R, McNamara JO
JournalNature
Volume538
Issue7623
Pagination99-103
Date Published2016 Oct 06
ISSN1476-4687
KeywordsAnimals, Autocrine Communication, Brain-Derived Neurotrophic Factor, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Dendritic Spines, Enzyme Activation, Female, Fluorescence Resonance Energy Transfer, Glutamic Acid, Green Fluorescent Proteins, HeLa Cells, Hippocampus, Humans, Long-Term Potentiation, Male, Membrane Glycoproteins, Mice, Mice, Inbred C57BL, Microscopy, Electron, Microscopy, Fluorescence, Multiphoton, Post-Synaptic Density, Protein-Tyrosine Kinases, Pyramidal Cells, Rats, Receptors, N-Methyl-D-Aspartate, Signal Transduction, Tissue Culture Techniques
Abstract

Brain-derived neurotrophic factor (BDNF) and its receptor TrkB are crucial for many forms of neuronal plasticity, including structural long-term potentiation (sLTP), which is a correlate of an animal's learning. However, it is unknown whether BDNF release and TrkB activation occur during sLTP, and if so, when and where. Here, using a fluorescence resonance energy transfer-based sensor for TrkB and two-photon fluorescence lifetime imaging microscopy, we monitor TrkB activity in single dendritic spines of CA1 pyramidal neurons in cultured murine hippocampal slices. In response to sLTP induction, we find fast (onset < 1 min) and sustained (>20 min) activation of TrkB in the stimulated spine that depends on NMDAR (N-methyl-d-aspartate receptor) and CaMKII signalling and on postsynaptically synthesized BDNF. We confirm the presence of postsynaptic BDNF using electron microscopy to localize endogenous BDNF to dendrites and spines of hippocampal CA1 pyramidal neurons. Consistent with these findings, we also show rapid, glutamate-uncaging-evoked, time-locked BDNF release from single dendritic spines using BDNF fused to superecliptic pHluorin. We demonstrate that this postsynaptic BDNF-TrkB signalling pathway is necessary for both structural and functional LTP. Together, these findings reveal a spine-autonomous, autocrine signalling mechanism involving NMDAR-CaMKII-dependent BDNF release from stimulated dendritic spines and subsequent TrkB activation on these same spines that is crucial for structural and functional plasticity.

DOI10.1038/nature19766
Alternate JournalNature
PubMed ID27680698
PubMed Central IDPMC5398094
Grant ListR01 MH080047 / MH / NIMH NIH HHS / United States
DP1 NS096787 / NS / NINDS NIH HHS / United States
F31 NS078847 / NS / NINDS NIH HHS / United States
R01 NS056217 / NS / NINDS NIH HHS / United States
R01 DA008259 / DA / NIDA NIH HHS / United States
R01 HL098351 / HL / NHLBI NIH HHS / United States
R01 NS030687 / NS / NINDS NIH HHS / United States
P01 HL096571 / HL / NHLBI NIH HHS / United States
R01 NS068410 / NS / NINDS NIH HHS / United States
T32 GM007105 / GM / NIGMS NIH HHS / United States