Autocrine BDNF-TrkB signalling within a single dendritic spine.
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.
Neurobiology Department, Duke University Medical Center, Research Drive, Durham, North Carolina 27710, USA.
Stephen C
SC
Harward
Neurobiology Department, Duke University Medical Center, Research Drive, Durham, North Carolina 27710, USA.
Nathan G
NG
Hedrick
Neurobiology Department, Duke University Medical Center, Research Drive, Durham, North Carolina 27710, USA.
Charles E
CE
Hall
Max Planck Florida Institute for Neuroscience, 1 Max Planck Way, Florida 33458, USA.
Paula
P
Parra-Bueno
Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, 407 East 61st St, New York 10065, USA.|Laboratory of Neuroendocrinology, The Rockefeller University, 1230 York Avenue, New York 10065, USA.
Teresa A
TA
Milner
Neurobiology Department, Duke University Medical Center, Research Drive, Durham, North Carolina 27710, USA.
Enhui
E
Pan
Max Planck Florida Institute for Neuroscience, 1 Max Planck Way, Florida 33458, USA.
Tal
T
Laviv
Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, 407 East 61st St, New York 10065, USA.|Department of Medicine, Weill Cornell Medicine, 1300 York Avenue, New York 10065, USA.
Barbara L
BL
Hempstead
Neurobiology Department, Duke University Medical Center, Research Drive, Durham, North Carolina 27710, USA.|Max Planck Florida Institute for Neuroscience, 1 Max Planck Way, Florida 33458, USA.
Ryohei
R
Yasuda
Neurobiology Department, Duke University Medical Center, Research Drive, Durham, North Carolina 27710, USA.
James O
JO
McNamara
D000818:Animals; D019898:Autocrine Communication; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D049229:Dendritic Spines / Q000378:metabolism* / Q000648:ultrastructure; D004789:Enzyme Activation; D005260:Female; D031541:Fluorescence Resonance Energy Transfer; D018698:Glutamic Acid / Q000378:metabolism; D049452:Green Fluorescent Proteins; D006367:HeLa Cells; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism / Q000648:ultrastructure; D006801:Humans; D017774:Long-Term Potentiation; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008854:Microscopy, Electron; D036641:Microscopy, Fluorescence, Multiphoton; D057907:Post-Synaptic Density / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D017966:Pyramidal Cells / Q000378:metabolism / Q000648:ultrastructure; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D015398:Signal Transduction; D046509:Tissue Culture Techniques; D020813:Receptor, trkB
D019208:Brain-Derived Neurotrophic Factor; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D018698:Glutamic Acid; D049452:Green Fluorescent Proteins; D008562:Membrane Glycoproteins; D011505:Protein-Tyrosine Kinases; D016194:Receptors, N-Methyl-D-Aspartate; C485187:PHluorin; C064371:Ntrk2 protein, mouse; D020813:Receptor, trkB
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