Synapsins regulate brain‐derived neurotrophic factor‐mediated synaptic potentiation and axon elongation by acting on membrane rafts

In neurons, intracellular membrane rafts are essential for specific actions of brain‐derived neurotrophic factor (BDNF), which include the regulation of axon outgrowth, growth cone turning and synaptic transmission. Virtually, all the actions of BDNF are mediated by binding to its receptor, TrkB. Th...

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Bibliographic Details
Published in:The European journal of neuroscience 2017-04, Vol.45 (8), p.1085-1101
Main Authors: Kao, Hung‐Teh, Ryoo, Kanghyun, Lin, Albert, Janoschka, Stephen R., Augustine, George J., Porton, Barbara, Kano, Masanobu
Format: Article
Language:English
Subjects:
Animals
Axonogenesis
Brain - cytology
Brain - metabolism
Brain-derived neurotrophic factor
Brain-Derived Neurotrophic Factor - metabolism
Cell Enlargement
Cell Line, Tumor
Cells, Cultured
Cholesterol
Cholesterol - metabolism
Elongation
Fyn protein
Growth cones
Humans
Intracellular
lipid
Lipid composition
Lipid rafts
Lipids
Localization
Membrane Microdomains - metabolism
Membrane Potentials - physiology
Mice, Inbred C57BL
Mice, Knockout
mouse
Neuroblastoma
Neuroblasts
neurodevelopment
Neuroglia - cytology
Neuroglia - metabolism
Neurons
Neurons - metabolism
Neurons - physiology
Phospholipids
Phospholipids - metabolism
Phosphoproteins
Potentiation
Promotion
Protein-tyrosine kinase
Proto-Oncogene Proteins c-fyn - metabolism
Receptor, trkB - metabolism
signal transduction
Synapses - metabolism
Synapsin
Synapsins - genetics
Synapsins - metabolism
Synaptic transmission
Synaptic Transmission - physiology
Synaptogenesis
TrkB receptors
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Summary:In neurons, intracellular membrane rafts are essential for specific actions of brain‐derived neurotrophic factor (BDNF), which include the regulation of axon outgrowth, growth cone turning and synaptic transmission. Virtually, all the actions of BDNF are mediated by binding to its receptor, TrkB. The association of TrkB with the tyrosine kinase, Fyn, is critical for its localization to intracellular membrane rafts. Here, we show that synapsins, a family of highly amphipathic neuronal phosphoproteins, regulate membrane raft lipid composition and consequently, the ability of BDNF to regulate axon/neurite development and potentiate synaptic transmission. In the brains of mice lacking all synapsins, the expression of both BDNF and TrkB were increased, suggesting that BDNF/TrkB‐mediated signaling is impaired. Consistent with this finding, synapsin‐depleted neurons exhibit altered raft lipid composition, deficient targeting of Fyn to rafts, attenuated TrkB activation, and abrogation of BDNF‐stimulated axon outgrowth and synaptic potentiation. Conversely, overexpression of synapsins in neuroblastoma cells results in corresponding reciprocal changes in raft lipid composition, increased localization of Fyn to rafts and promotion of BDNF‐stimulated neurite formation. In the presence of synapsins, the ratio of cholesterol to estimated total phospholipids converged to 1, suggesting that synapsins act by regulating the ratio of lipids in intracellular membranes, thereby promoting lipid raft formation. These studies reveal a mechanistic link between BDNF and synapsins, impacting early development and synaptic transmission. We investigated the role of synapsins in neuronal development. The results show that synapsins regulate intracellular membrane raft lipid composition by restricting the ratio of cholesterol to total phospholipids, thereby promoting the localization of Fyn/TrkB to rafts, and subsequent activation of TrkB by BDNF. Consistent with these results, synapsins are required for BDNF‐stimulated axon outgrowth and synaptic potentiation, thus revealing mechanistic links between BDNF and synapsins.
ISSN:0953-816X
1460-9568
DOI:10.1111/ejn.13552