Ma J, Duan Y, Qin Z, Wang J, Liu W, Xu M, Zhou S, Cao X
Key Laboratory of Brain Functional Genomics (East China Normal University), Ministry of Education, Shanghai Key Laboratory of Brain Functional Genomics (East China Normal University), School of Life Sciences, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China.
Key Laboratory of Brain Functional Genomics (East China Normal University), Ministry of Education, Shanghai Key Laboratory of Brain Functional Genomics (East China Normal University), School of Life Sciences, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China.
Neuroscience. 2015 Dec 3;310:528-40. doi: 10.1016/j.neuroscience.2015.09.051. Epub 2015 Sep 28.
The medial prefrontal cortex (mPFC) participates in the behavioral flexibility. As a major downstream molecule in the NMDA receptor signaling, alpha-Ca(2+)/calmodulin-dependent protein kinase II (αCaMKII) is crucial for hippocampal long-term potentiation (LTP) and hippocampus-related memory. However, the role of αCaMKII in mPFC-related behavioral flexibility and mPFC synaptic plasticity remains elusive. In the present study, using chemical-genetic approaches to temporally up-regulate αCaMKII activity, we found that αCaMKII-F89G transgenic mice exhibited impaired behavioral flexibility in Y-water maze arm reversal task. Notably, in vitro electrophysiological analysis showed normal basal synaptic transmission, LTP and depotentiation, but selectively impaired NMDAR-dependent long-term depression (LTD) in the mPFC of αCaMKII-F89G transgenic mice. In accordance with the deficit in NMDAR-dependent LTD, αCaMKII-F89G transgenic mice exhibited impaired AMPAR internalization during NMDAR-dependent chemical LTD expression in the mPFC. Furthermore, the above deficits in behavioral flexibility, NMDAR-dependent LTD and AMPAR internalization could all be reversed by 1-naphthylmethyl (NM)-PP1, a specific inhibitor of exogenous αCaMKII-F89G activity. Taken together, our results for the first time indicate that αCaMKII overexpression in the forebrain impairs behavioral flexibility and NMDAR-dependent LTD in the mPFC, and supports the notion that there is a close relationship between NMDAR-dependent LTD and behavioral flexibility.
内侧前额叶皮质（mPFC）参与行为灵活性。作为NMDA受体信号通路中的主要下游分子，α-钙调蛋白依赖性蛋白激酶II（αCaMKII）对海马体长期增强（LTP）和海马体相关记忆至关重要。然而，αCaMKII在mPFC相关行为灵活性和mPFC突触可塑性中的作用仍不清楚。在本研究中，我们使用化学遗传学方法暂时上调αCaMKII活性，发现αCaMKII-F89G转基因小鼠在Y型水迷宫臂反转任务中表现出行为灵活性受损。值得注意的是，体外电生理分析显示基础突触传递、LTP和去增强正常，但αCaMKII-F89G转基因小鼠的mPFC中NMDAR依赖性长时程抑制（LTD）选择性受损。与NMDAR依赖性LTD的缺陷一致，αCaMKII-F89G转基因小鼠在mPFC中NMDAR依赖性化学LTD表达期间表现出AMPA受体内化受损。此外，行为灵活性、NMDAR依赖性LTD和AMPA受体内化的上述缺陷均可被外源性αCaMKII-F89G活性的特异性抑制剂1-萘甲基（NM）-PP1逆转。综上所述，我们的结果首次表明前脑αCaMKII过表达会损害mPFC中的行为灵活性和NMDAR依赖性LTD，并支持NMDAR依赖性LTD与行为灵活性之间存在密切关系的观点。
