Department of Cell and Developmental Biology, University College London, London WC1E 6BT, UK.
Department of Neuroscience, Physiology and Pharmacology, University College London, London WC1E 6BT, UK.
Cell Rep. 2018 Apr 24;23(4):1060-1071. doi: 10.1016/j.celrep.2018.03.119.
The structural and functional plasticity of synapses is critical for learning and memory. Long-term potentiation (LTP) induction promotes spine growth and AMPAR accumulation at excitatory synapses, leading to increased synaptic strength. Glutamate initiates these processes, but the contribution from extracellular modulators is not fully established. Wnts are required for spine formation; however, their impact on activity-mediated spine plasticity and AMPAR localization is unknown. We found that LTP induction rapidly increased synaptic Wnt7a/b protein levels. Acute blockade of endogenous Wnts or loss of postsynaptic Frizzled-7 (Fz7) receptors impaired LTP-mediated synaptic strength, spine growth, and AMPAR localization at synapses. Live imaging of SEP-GluA1 and single-particle tracking revealed that Wnt7a rapidly promoted synaptic AMPAR recruitment and trapping. Wnt7a, through Fz7, induced CaMKII-dependent loss of SynGAP from spines and increased extrasynaptic AMPARs by PKA phosphorylation. We identify a critical role for Wnt-Fz7 signaling in LTP-mediated synaptic accumulation of AMPARs and spine plasticity.
突触的结构和功能可塑性对于学习和记忆至关重要。长时程增强（LTP）诱导促进兴奋性突触处的棘突生长和 AMPAR 积累，从而增强突触强度。谷氨酸引发这些过程，但细胞外调节剂的贡献尚未完全确定。Wnts 对于棘突形成是必需的；然而，它们对活动介导的棘突可塑性和 AMPAR 定位的影响尚不清楚。我们发现 LTP 诱导可迅速增加突触 Wnt7a/b 蛋白水平。内源性 Wnts 的急性阻断或突触后 Frizzled-7（Fz7）受体的缺失损害了 LTP 介导的突触强度、棘突生长和 AMPAR 在突触处的定位。SEP-GluA1 的实时成像和单颗粒跟踪显示，Wnt7a 可迅速促进突触 AMPAR 的募集和捕获。Wnt7a 通过 Fz7 诱导 CaMKII 依赖性 SynGAP 从棘突中丢失，并通过 PKA 磷酸化增加突触外 AMPAR。我们确定了 Wnt-Fz7 信号在 LTP 介导的 AMPAR 突触积累和棘突可塑性中的关键作用。
