Wip1 phosphatase modulates both long-term potentiation and long-term depression through the dephosphorylation of CaMKII

Synaptic plasticity is an important mechanism that underlies learning and cognition. Protein phosphorylation by kinases and dephosphorylation by phosphatases play critical roles in the activity-dependent alteration of synaptic plasticity. In this study, we report that Wip1, a protein phosphatase, is essential for long-term potentiation (LTP) and long-term depression (LTD) processes. Wip1-deletion suppresses LTP and enhances LTD in the hippocampus CA1 area. Wip1 deficiency-induced aberrant elevation of CaMKII T286/287 and T305 phosphorylation underlies these dysfunctions. Moreover, we showed that Wip1 modulates CaMKII dephosphorylation. Wip1^−/− mice exhibit abnormal GluR1 membrane expression, which could be reversed by the application of a CaMKII inhibitor, indicating that Wip1/CaMKII signaling is crucial for synaptic plasticity. Together, our results demonstrate that Wip1 phosphatase plays a vital role in regulating hippocampal synaptic plasticity by modulating the phosphorylation of CaMKII.

突触可塑性（Synaptic plasticity）是支撑学习与认知过程的核心机制。蛋白激酶（kinases）介导的蛋白质磷酸化与蛋白磷酸酶（phosphatases）介导的去磷酸化，在突触可塑性的活性依赖性重塑中发挥关键调控作用。本研究发现，作为一种蛋白磷酸酶的Wip1，对长时程增强（long-term potentiation, LTP）与长时程抑制（long-term depression, LTD）过程均不可或缺。在海马CA1脑区中，Wip1基因敲除可抑制LTP并增强LTD。Wip1缺失所导致的钙/钙调蛋白依赖性蛋白激酶Ⅱ（CaMKII）T286/287与T305位点磷酸化水平异常升高，是上述突触功能异常的分子基础。此外，本研究证实Wip1可调控CaMKII的去磷酸化过程。Wip1基因敲除小鼠表现出谷氨酸受体1（GluR1）膜表达异常，该表型可通过施加CaMKII抑制剂得以逆转，这表明Wip1/CaMKII信号通路对突触可塑性至关重要。综上，本研究结果证实，Wip1磷酸酶通过调控CaMKII的磷酸化水平，在海马突触可塑性的调控中发挥关键作用。