Department of Cell and Developmental Biology, University College London, London WC1E 6BT, United Kingdom.
Proc Natl Acad Sci U S A. 2011 Jun 28;108(26):10732-7. doi: 10.1073/pnas.1018132108. Epub 2011 Jun 13.
The balance between excitatory and inhibitory synapses is crucial for normal brain function. Wnt proteins stimulate synapse formation by increasing synaptic assembly. However, it is unclear whether Wnt signaling differentially regulates the formation of excitatory and inhibitory synapses. Here, we demonstrate that Wnt7a preferentially stimulates excitatory synapse formation and function. In hippocampal neurons, Wnt7a increases the number of excitatory synapses, whereas inhibitory synapses are unaffected. Wnt7a or postsynaptic expression of Dishevelled-1 (Dvl1), a core Wnt signaling component, increases the frequency and amplitude of miniature excitatory postsynaptic currents (mEPSCs), but not miniature inhibitory postsynaptic currents (mIPSCs). Wnt7a increases the density and maturity of dendritic spines, whereas Wnt7a-Dvl1-deficient mice exhibit defects in spine morphogenesis and mossy fiber-CA3 synaptic transmission in the hippocampus. Using a postsynaptic reporter for Ca(2+)/Calmodulin-dependent protein kinase II (CaMKII) activity, we demonstrate that Wnt7a rapidly activates CaMKII in spines. Importantly, CaMKII inhibition abolishes the effects of Wnt7a on spine growth and excitatory synaptic strength. These data indicate that Wnt7a signaling is critical to regulate spine growth and synaptic strength through the local activation of CaMKII at dendritic spines. Therefore, aberrant Wnt7a signaling may contribute to neurological disorders in which excitatory signaling is disrupted.
兴奋性和抑制性突触之间的平衡对于正常的大脑功能至关重要。Wnt 蛋白通过增加突触组装来刺激突触形成。然而，目前尚不清楚 Wnt 信号是否会差异调节兴奋性和抑制性突触的形成。在这里，我们证明 Wnt7a 优先刺激兴奋性突触的形成和功能。在海马神经元中，Wnt7a 增加了兴奋性突触的数量，而抑制性突触不受影响。Wnt7a 或核心 Wnt 信号成分 Dishevelled-1 (Dvl1) 的突触后表达增加了微小兴奋性突触后电流 (mEPSC) 的频率和幅度，但不增加微小抑制性突触后电流 (mIPSC)。Wnt7a 增加了树突棘的密度和成熟度，而 Wnt7a-Dvl1 缺陷型小鼠在海马体中表现出棘突形态发生和苔藓纤维-CA3 突触传递的缺陷。使用 Ca(2+)/钙调蛋白依赖性蛋白激酶 II (CaMKII) 活性的突触后报告器，我们证明 Wnt7a 可快速激活棘突中的 CaMKII。重要的是，CaMKII 抑制消除了 Wnt7a 对棘突生长和兴奋性突触强度的影响。这些数据表明，Wnt7a 信号通过在树突棘中局部激活 CaMKII 对于调节棘突生长和突触强度至关重要。因此，异常的 Wnt7a 信号可能导致兴奋性信号中断的神经紊乱。
