Autocrine BDNF-TrkB signalling within a single dendritic spine
Open accessAbstract
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.
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Activity-dependent BDNF release activates TrkB in an autocrine loop that is essential for both structural and functional long-term potentiation.
“At the level of individual spines, activity-dependent BDNF release activates TrkB in an autocrine loop that is essential for both structural and functional long-term potentiation [105,107,108].”
From Synaptic Plasticity—Intrinsic Excitability and Antidepressant Discovery (2026) · cites this paper as [107]
This BDNF is released into the synaptic cleft of the same synapse, where it activates TrkB receptors and induces the actin-stabilizing GTPases Cdc42 and Rac.
“This BDNF is released into the synaptic cleft of the same synapse, where it activates TrkB receptors and induces the actin-stabilizing GTPases Cdc42 and Rac (48) (Fig. 2B, 3 and 4), much like Reelin during axogenesis (8) (Fig. 1D).”
From Reelin: Neurodevelopmental Architect and Homeostatic Regulator of Excitatory Synapses (2017) · cites this paper as [48]
Focal uncaging of glutamate revealed that Ca2+ influx from NMDAR can increase BDNF rapidly and locally.
“Interestingly, experiments utilizing the focal uncaging of glutamate have revealed that Ca 2ϩ influx from NMDAR can increase BDNF rapidly and locally.”
From Reelin: Neurodevelopmental Architect and Homeostatic Regulator of Excitatory Synapses (2017) · cites this paper as [48]
BDNF can be released at the activated synapse and bind TrkB receptors, which promote actin stability through Cdc42 and Rac activity.
“This BDNF can be released at the activated synapse and bind TrkB receptors (3), which promote actin stability through Cdc42 and Rac activity (4) (48).”
From Reelin: Neurodevelopmental Architect and Homeostatic Regulator of Excitatory Synapses (2017) · cites this paper as [48]
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“This BDNF is released into the synaptic cleft of the same synapse, where it activates TrkB receptors and induces the actin-stabilizing GTPases Cdc42 and Rac (48) (Fig.”
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- Authors
- Harward, S. C., Hedrick, N. G., Hall, C. E., Parra-Bueno, P., Milner, T. A., Pan, E., Laviv, T., Hempstead, B. L., Yasuda, R., & McNamara, J. O.
- Affiliations
- Duke University (US)
- Max Planck Florida Institute for Neuroscience (US)
- Weill Cornell Medicine (US)
- Corresponding author
- Yasuda, Ryohei
- ORCID
- Venue
- Nature
- Published
- 2016-09-28
- Volume
- 538
- Issue
- 7623
- Pages
- 99-103
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5398094
- OpenAlex
- W2525665487
- Cited by
- 325
- References
- 40
- Citations by year
- 2026: 16 · 2025: 21 · 2024: 29 · 2023: 34 · 2022: 33 · 2021: 50 · 2020: 35 · 2019: 38 · 2018: 38 · 2017: 25 · 2016: 5 · 2014: 1
- FWCI
- 19.82
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Max Planck Digital Library (submittedVersion)
- Funders
- National Heart, Lung, and Blood Institute (P01HL096571, R01HL098351)
- National Institute of Mental Health (R01MH080047)
- National Institute on Drug Abuse (R01DA008259)
- National Institute of General Medical Sciences (T32GM007105)
- National Institute of Neurological Disorders and Stroke (F31NS078847, R01NS068410, R01NS030687, R01NS056217, DP1NS096787)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Keywords
- TrkB receptor, dendritic spines, NMDA receptor, synaptic plasticity, Rac1, RhoA, Cdc42, small GTPases, CA1 pyramidal neurons, signaling specificity
- MeSH terms
- Animals, Enzyme Activation, Female, HeLa Cells, Hippocampus, Humans, Male, Membrane Glycoproteins, Mice, Inbred C57BL, Microscopy, Electron, Protein-Tyrosine Kinases, Signal Transduction, Receptors, N-Methyl-D-Aspartate, Long-Term Potentiation, Pyramidal Cells, Glutamic Acid, Brain-Derived Neurotrophic Factor, Autocrine Communication, Receptor, trkB, Fluorescence Resonance Energy Transfer, Microscopy, Fluorescence, Multiphoton, Tissue Culture Techniques, Dendritic Spines, Green Fluorescent Proteins, Mice, Rats, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Post-Synaptic Density
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