McLeod Faye, Boyle Kieran, Marzo Aude, Martin-Flores Nuria, Moe Thaw Zin, Palomer Ernest, Gibb Alasdair J, Salinas Patricia C
Department of Cell and Developmental Biology, University College London, London, United Kingdom.
Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom.
Front Synaptic Neurosci. 2020 Sep 4;12:575863. doi: 10.3389/fnsyn.2020.575863. eCollection 2020.
Structural plasticity of synapses correlates with changes in synaptic strength. Dynamic modifications in dendritic spine number and size are crucial for long-term potentiation (LTP), the cellular correlate of learning and memory. Recent studies have suggested the generation of multi-innervated spines (MIS), in the form of several excitatory presynaptic inputs onto one spine, are crucial for hippocampal memory storage. However, little is known about the molecular mechanisms underlying MIS formation and their contribution to LTP. Using 3D enhanced resolution confocal images, we examined the contribution of Wnt synaptic modulators in MIS formation in the context of LTP. We show that blockage of endogenous Wnts with specific Wnt antagonists supresses the formation of MIS upon chemical LTP induction in cultured hippocampal neurons. Gain- and loss-of-function studies demonstrate that Wnt7a signaling promotes MIS formation through the postsynaptic Wnt scaffold protein Disheveled 1 (Dvl1) by stimulating neuronal nitric oxide (NO) synthase (nNOS). Subsequently, NO activates soluble guanylyl cyclase (sGC) to increase MIS formation. Consistently, we observed an enhanced frequency and amplitude of excitatory postsynaptic currents. Collectively, our findings identify a unique role for Wnt secreted proteins through nNOS/NO/sGC signaling to modulate MIS formation during LTP.
突触的结构可塑性与突触强度的变化相关。树突棘数量和大小的动态改变对于长时程增强（LTP）至关重要，LTP是学习和记忆的细胞关联物。最近的研究表明，多神经支配棘（MIS）的产生，即一个棘上有多个兴奋性突触前输入的形式，对于海马体记忆存储至关重要。然而，关于MIS形成的分子机制及其对LTP的贡献知之甚少。利用三维增强分辨率共聚焦图像，我们在LTP的背景下研究了Wnt突触调节剂在MIS形成中的作用。我们发现，用特异性Wnt拮抗剂阻断内源性Wnt会抑制培养的海马神经元在化学LTP诱导时MIS的形成。功能获得和功能缺失研究表明，Wnt7a信号通过刺激神经元型一氧化氮合酶（nNOS），通过突触后Wnt支架蛋白Dishevelled 1（Dvl1）促进MIS形成。随后，NO激活可溶性鸟苷酸环化酶（sGC）以增加MIS形成。一致地，我们观察到兴奋性突触后电流的频率和幅度增加。总的来说，我们的研究结果确定了Wnt分泌蛋白通过nNOS/NO/sGC信号在LTP期间调节MIS形成中的独特作用。
