Abstract
Pro- and mature brain-derived neurotrophic factor (BDNF) activate two distinct receptors: p75 neurotrophin receptor (p75NTR) and TrkB. Mature BDNF facilitates hippocampal synaptic potentiation through TrkB. Here we report that proBDNF, by activating p75NTR, facilitates hippocampal long-term depression (LTD). Electron microscopy showed that p75NTR localized in dendritic spines, in addition to afferent terminals, of CA1 neurons. Deletion of p75NTR in mice selectively impaired the NMDA receptor–dependent LTD, without affecting other forms of synaptic plasticity. p75NTR−/− mice also showed a decrease in the expression of NR2B, an NMDA receptor subunit uniquely involved in LTD. Activation of p75NTR by proBDNF enhanced NR2B-dependent LTD and NR2B-mediated synaptic currents. These results show a crucial role for proBDNF-p75NTR signaling in LTD and its potential mechanism, and together with the finding that mature BDNF promotes synaptic potentiation, suggest a bidirectional regulation of synaptic plasticity by proBDNF and mature BDNF.
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Acknowledgements
This work is supported by funds from National Institute of Child Health and Human Development intramural program (to B.L.), and US National Institutes of Health grants NS30658 (to B.L.H.) and HL18974 (to T.A.M.). N.H.W. is supported by fellowships from Alberta Heritage Foundation for Medical Research and Natural Sciences and Engineering Research Council of Canada. We would like to thank K. Sakata, J. Chang and K. Pelkey for advice and assistance. We also thank L. Tessarollo for providing p75NTR−/− mice and L. Reichardt for the p75NTR-blocking REX antibody.
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Supplementary information
Supplementary Fig. 1
Hippocampal LTD induced by LFS is NMDA receptor-dependent. (PDF 177 kb)
Supplementary Fig. 2
Ultrastructural localization of p75NTR immunoreactivity in the hippocampus of p75NTR+/+ (i.e., Ngfr+/+) mice. (PDF 4149 kb)
Supplementary Fig. 3
proBDNF does not affect hippocampal LTP. (PDF 101 kb)
Supplementary Fig. 4
Attenuated expression of NR2B in area CA1 of p75NTR−/− (i.e., Ngfr−/−) hippocampal slices. (PDF 2513 kb)
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Woo, N., Teng, H., Siao, CJ. et al. Activation of p75NTR by proBDNF facilitates hippocampal long-term depression. Nat Neurosci 8, 1069–1077 (2005). https://doi.org/10.1038/nn1510
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DOI: https://doi.org/10.1038/nn1510
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