Overexpression of βCaMKII impairs behavioral flexibility and NMDAR-dependent long-term depression in the dentate gyrus
Overexpression of βCaMKII impairs behavioral flexibility and NMDAR-dependent long-term depression in the dentate gyrus
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DOI：
10.1016/j.neuropharm.2016.12.013
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发表时间：
2017-04
影响因子：
4.7
通讯作者：
Pengcheng Yin;Hao Xu-;Qi Wang;Jiayue Wang;Liang Yin;Meichen Xu;Zhen Xie;Wen-zhuang Liu;Xiaohua Ca
中科院分区：
文献类型：
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作者：
Pengcheng Yin;Hao Xu-;Qi Wang;Jiayue Wang;Liang Yin;Meichen Xu;Zhen Xie;Wen-zhuang Liu;Xiaohua Ca
行为灵活性与齿状回 (DG) 功能和长期抑郁 (LTD) 非常接近，但 DG LTD 在行为灵活性中的作用迄今尚未被探索。尽管 α-Ca2+/钙调蛋白依赖性蛋白激酶 II (CaMKII) 的功能已被广泛研究，但 βCaMKII（CaMKII 全酶的组成部分）在 LTD 和行为灵活性中的作用尚未在体内研究。这里使用βCaMKII-F90G转基因（TG）小鼠，其中βCaMKII的可诱导和可逆过度表达仅限于齿状回（DG），我们发现TG小鼠在两个逆转任务中表现出有缺陷的行为灵活性，并且DG内侧穿通路径（MPP）中的N-甲基-d-天冬氨酸受体（NMDAR）依赖性LTD严重受损。与 NMDAR-LTD 的缺陷一致，TG 小鼠的 NMDAR-LTD 期间，GluA1-Ser845、GluA1-Ser831 去磷酸化和 α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体 (AMPAR) 内化也受到破坏。此外，这些缺陷是由于 TG 小鼠中蛋白磷酸酶 (PP) 1/2A 和糖原合成激酶 3 beta (GSK3β) 活性降低以及突触 stargazin 过度表达所致。重要的是，上述所有缺陷都可以通过 1-萘甲基 (NM)-PP1（一种外源 βCaMKII-F90G 的特异性抑制剂）来逆转。综上所述，我们的研究结果首次证明βCaMKII过表达会损害DG MPP中的行为灵活性和NMDAR依赖性LTD，这进一步证实了NMDAR依赖性LTD与行为灵活性之间的密切关系。
Behavioral flexibility is in close proximity to dentate gyrus (DG) function and long-term depression (LTD), but the role of DG LTD in behavioral flexibility has hitherto been unexplored. Although the functions of alpha-Ca2+/calmodulin-dependent protein kinase II (CaMKII) have been studied extensively, the role of βCaMKII, a constituent of the CaMKII holoenzyme, in LTD and behavioral flexibility has not been investigated in vivo. Here using the βCaMKII-F90G transgenic (TG) mice, in which the inducible and reversible overexpression of βCaMKII is restricted to dentate gyrus (DG), we found that TG mice exhibited defective behavioral flexibility in two reversal tasks and seriously impairedN-methyl-d-aspartic acid receptor (NMDAR)-dependent LTD in DG medial perforant path (MPP). Consistent with the deficit in NMDAR-LTD, GluA1-Ser845, GluA1-Ser831 dephosphorylation and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) internalization were also disrupted during NMDAR-LTD in TG mice. Furthermore, these deficits were due to decreased activities of protein phosphatases (PP) 1/2A and glycogen synthesis kinase 3 beta (GSK3β), and overexpressed synaptic stargazin in TG mice. Importantly, all the deficits above could be reversed by 1-naphthylmethyl (NM)-PP1, a specific inhibitor of the exogenous βCaMKII-F90G. Taken together, our findings for the first time demonstrate that βCaMKII overexpression impairs behavioral flexibility and NMDAR-dependent LTD in DG MPP, which further confirms the close relationship between NMDAR-dependent LTD and behavioral flexibility.