Network compensation of cyclic GMP-dependent protein kinase II knockout in the hippocampus by Ca2+-permeable AMPA receptors
Network compensation of cyclic GMP-dependent protein kinase II knockout in the hippocampus by Ca2+-permeable AMPA receptors
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DOI：
10.1073/pnas.1417498112
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发表时间：
2015-03-10
影响因子：
11.1
通讯作者：
Ziff, Edward B.
中科院分区：
文献类型：
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作者：
Kim, Seonil;Titcombe, Roseann F.;Ziff, Edward B.
基因敲除（KO）并不总是导致表型变化，可能是由于功能补偿机制。我们研究了缺乏cGMP依赖性激酶II（cGKII）的小鼠，cGKII磷酸化GluA 1，AMPA受体（AMPAR）的亚基，并通过AMPAR运输促进海马长时程增强（LTP）。急性cGKII抑制显著降低LTP，而cGKII KO小鼠未显示LTP损伤。值得注意的是，密切相关的激酶cGKI不能补偿cGKII KO。在这里，我们描述了一个以前未确定的途径在KO海马，提供功能补偿时观察到的LTP损伤cGKII急性抑制。我们发现，在培养的cGKII KO海马神经元中，1，4，5-三磷酸肌醇受体的cGKII依赖性磷酸化降低，从而减少细胞质Ca 2+信号。这导致钙调磷酸酶活性降低，从而稳定GluA 1磷酸化并促进Ca 2+渗透性AMPAR的突触表达，这反过来又诱导了先前未鉴定的LTP形式作为KO海马中的代偿反应。钙调神经磷酸酶依赖性Ca 2+渗透AMPAR的表达也被用于活动依赖性稳态突触可塑性。因此，在活动减少期间使用的稳态机制为cGKII KO海马中的基因KO提供功能补偿。
Gene knockout (KO) does not always result in phenotypic changes, possibly due to mechanisms of functional compensation. We have studied mice lacking cGMP-dependent kinase II (cGKII), which phosphorylates GluA1, a subunit of AMPA receptors (AMPARs), and promotes hippocampal long-term potentiation (LTP) through AMPAR trafficking. Acute cGKII inhibition significantly reduces LTP, whereas cGKII KO mice show no LTP impairment. Significantly, the closely related kinase, cGKI, does not compensate for cGKII KO. Here, we describe a previously unidentified pathway in the KO hippocampus that provides functional compensation for the LTP impairment observed when cGKII is acutely inhibited. We found that in cultured cGKII KO hippocampal neurons, cGKII-dependent phosphorylation of inositol 1,4,5-trisphosphate receptors was decreased, reducing cytoplasmic Ca2+ signals. This led to a reduction of calcineurin activity, thereby stabilizing GluA1 phosphorylation and promoting synaptic expression of Ca2+-permeable AMPARs, which in turn induced a previously unidentified form of LTP as a compensatory response in the KO hippocampus. Calcineurin-dependent Ca2+-permeable AMPAR expression observed here is also used during activity-dependent homeostatic synaptic plasticity. Thus, a homeostatic mechanism used during activity reduction provides functional compensation for gene KO in the cGKII KO hippocampus.