PDF(Pubmed)
Abstract：
Synaptic plasticity, the process whereby neuronal connections are either strengthened or weakened in response to stereotyped forms of stimulation, is widely believed to represent the molecular mechanism that underlies learning and memory. The holoenzyme calcium/calmodulin-dependent protein kinase II (CaMKII) plays a well-established and critical role in the induction of a variety of forms of synaptic plasticity such as long-term potentiation (LTP), long-term depression (LTD) and depotentiation. Previously, we identified the GTPase Rem2 as a potent, endogenous inhibitor of CaMKII. Here, we report that knock out of Rem2 enhances LTP at the Schaffer collateral to CA1 synapse in hippocampus, consistent with an inhibitory action of Rem2 on CaMKII in vivo. Further, re-expression of WT Rem2 rescues the enhanced LTP observed in slices obtained from Rem2 conditional knock out (cKO) mice, while expression of a mutant Rem2 construct that is unable to inhibit CaMKII in vitro fails to rescue increased LTP. In addition, we demonstrate that CaMKII and Rem2 interact in dendritic spines using a 2pFLIM-FRET approach. Taken together, our data lead us to propose that Rem2 serves as a brake on synaptic potentiation via inhibition of CaMKII activity. Further, the enhanced LTP phenotype we observe in Rem2 cKO slices reveals a previously unknown role for Rem2 in the negative regulation of CaMKII function.
摘要：
突触可塑性,神经元连接因刻板的刺激形式而增强或减弱的过程，被广泛认为代表了学习和记忆的分子机制。全酶钙/钙调蛋白依赖性蛋白激酶II（CaMKII）在诱导各种形式的突触可塑性中起着公认的关键作用，例如长期增强（LTP），长期抑郁(LTD)和减势。以前,我们确定GTPaseRem2是一种有效的，内源性CaMKII抑制剂。这里,我们报告说，敲除Rem2增强了海马CA1突触的Schaffer侧支的LTP，与Rem2在体内对CaMKII的抑制作用一致。Further,WTRem2的再表达挽救了从Rem2条件性敲除（cKO）小鼠获得的切片中观察到的增强的LTP，而不能在体外抑制CaMKII的突变体Rem2构建体的表达未能挽救增加的LTP。此外,我们使用2pFLIM-FRET方法证明CaMKII和Rem2在树突棘中相互作用。一起来看,我们的数据使我们提出Rem2通过抑制CaMKII活性来抑制突触增强。Further,我们在Rem2cKO切片中观察到的增强的LTP表型揭示了Rem2在CaMKII功能负调节中的先前未知的作用。
