Kao Hung-Teh, Ryoo Kanghyun, Lin Albert, Janoschka Stephen R, Augustine George J, Porton Barbara
Department of Psychiatry and Human Behavior, Brown University, 171 Meeting Street, Room 187, Providence, RI, 02912, USA.
Butler Hospital, Providence, RI, USA.
Eur J Neurosci. 2017 Apr;45(8):1085-1101. doi: 10.1111/ejn.13552. Epub 2017 Mar 21.
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.
在神经元中，细胞内膜筏对于脑源性神经营养因子（BDNF）的特定作用至关重要，这些作用包括轴突生长、生长锥转向和突触传递的调节。实际上，BDNF的所有作用都是通过与它的受体TrkB结合来介导的。TrkB与酪氨酸激酶Fyn的结合对于其定位于细胞内膜筏至关重要。在这里，我们表明突触素，一类高度两亲性的神经元磷蛋白，调节膜筏脂质组成，从而调节BDNF调节轴突/神经突发育和增强突触传递的能力。在缺乏所有突触素的小鼠大脑中，BDNF和TrkB的表达均增加，这表明BDNF/TrkB介导的信号传导受损。与这一发现一致，缺乏突触素的神经元表现出膜筏脂质组成改变、Fyn定位于膜筏缺陷、TrkB激活减弱以及BDNF刺激的轴突生长和突触增强作用的消除。相反，在神经母细胞瘤细胞中过表达突触素会导致膜筏脂质组成相应的反向变化、Fyn定位于膜筏增加以及BDNF刺激的神经突形成增强。在有突触素存在的情况下，胆固醇与估计的总磷脂的比率收敛于1，这表明突触素通过调节细胞内膜中的脂质比率起作用，从而促进脂筏形成。这些研究揭示了BDNF与突触素之间的机制联系，影响早期发育和突触传递。
