title: Synapsins regulate brain-derived neurotrophic factor-mediated synaptic potentiation and axon elongation by acting on membrane rafts.
abstract: 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.
authors.affiliation: Department of Psychiatry and Human Behavior, Brown University, 171 Meeting Street, Room 187, Providence, RI, 02912, USA.|Butler Hospital, Providence, RI, USA.
authors.forename: Hung-Teh
authors.identifier: 0000-0002-5005-1493
authors.initials: HT
authors.lastname: Kao
authors.affiliation: Center for Functional Connectomics, Korea Institute of Science and Technology, Sungbukgu, Seoul, Korea.
authors.forename: Kanghyun
authors.initials: K
authors.lastname: Ryoo
authors.affiliation: Department of Psychiatry and Human Behavior, Brown University, 171 Meeting Street, Room 187, Providence, RI, 02912, USA.|Butler Hospital, Providence, RI, USA.
authors.forename: Albert
authors.initials: A
authors.lastname: Lin
authors.affiliation: Department of Psychiatry and Human Behavior, Brown University, 171 Meeting Street, Room 187, Providence, RI, 02912, USA.|Butler Hospital, Providence, RI, USA.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Janoschka
authors.affiliation: Center for Functional Connectomics, Korea Institute of Science and Technology, Sungbukgu, Seoul, Korea.|Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore.
authors.forename: George J
authors.initials: GJ
authors.lastname: Augustine
authors.affiliation: Department of Psychiatry and Human Behavior, Brown University, 171 Meeting Street, Room 187, Providence, RI, 02912, USA.|Butler Hospital, Providence, RI, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Porton
mesh_terms: D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D049108:Cell Enlargement; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D006801:Humans; D021962:Membrane Microdomains / Q000378:metabolism*; D008564:Membrane Potentials / Q000502:physiology*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009457:Neuroglia / Q000166:cytology / Q000378:metabolism; D009474:Neurons / Q000378:metabolism* / Q000502:physiology; D010743:Phospholipids / Q000378:metabolism; D051076:Proto-Oncogene Proteins c-fyn / Q000378:metabolism; D020813:Receptor, trkB / Q000378:metabolism; D013569:Synapses / Q000378:metabolism*; D016704:Synapsins / Q000235:genetics / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D010743:Phospholipids; D016704:Synapsins; D002784:Cholesterol; D020813:Receptor, trkB; C494957:FYN protein, human; C494960:Fyn protein, mouse; D051076:Proto-Oncogene Proteins c-fyn
keywords: lipid; mouse; neurodevelopment; signal transduction