Synapsins regulate BDNF-mediated synaptic potentiation and axon elongation by acting on membrane rafts

• Published in: The European journal of neuroscience Vol. 45; no. 8; pp. 1085 - 1101
• Main Authors: Kao, Hung-Teh, Ryoo, Kanghyun, Lin, Albert, Janoschka, Stephen R., Augustine, George J., Porton, Barbara
• Format: Journal Article
• Language: English
• Published: 21-03-2017
• ISSN: 0953-816X; 1460-9568
• DOI: 10.1111/ejn.13552

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.