Simvastatin treatment enhances NMDAR-mediated synaptic transmission by upregulating the surface distribution of the GluN2B subunit.
Simvastatin treatment enhances NMDAR-mediated synaptic transmission by upregulating the surface distribution of the GluN2B subunit.
复制标题
DOI：
10.1007/s10571-014-0051-z
复制
发表时间：
2014-07
影响因子：
4
通讯作者：
Li, Ling
中科院分区：
文献类型：
--
作者：
Parent, Marc-Alexander L. T.;Hottman, David A.;Cheng, Shaowu;Zhang, Wei;McMahon, Lori L.;Yuan, Li-Lian;Li, Ling
关键词：
他汀类药物对血浆胆固醇和冠心病的影响已被充分证明。然而，越来越多的证据表明，抑制甲羟戊酸途径可能提供独立的神经保护和促认知多效性作用，最有可能是通过抑制类异戊二烯，主要是焦磷酸法呢酯（FPP）和焦磷酸香叶基香叶基酯（GGPP）。FPP和GGPP是用于蛋白质异戊二烯化的异戊二烯基的主要供体。类异戊二烯可用性的调节影响一系列细胞过程，包括海马中的突触可塑性。我们以前的工作已经证明，辛伐他汀（SV）管理，改善海马依赖性空间记忆，挽救记忆缺陷的小鼠模型阿尔茨海默氏病。用SV处理海马脑片增强长时程增强（LTP），并且该效应依赖于Akt（蛋白激酶B）的激活。进一步的研究表明，SV诱导的海马LTP增强是通过消耗FPP和抑制法尼基化驱动的。在本研究中，我们报告的功能后果暴露于SV在细胞/突触和分子水平。虽然SV的应用对CA 1锥体神经元的固有膜特性没有影响，包括超极化激活的环核苷酸通道介导的凹陷电位，后超极化（AHP）和兴奋性，SV的应用增强了N-甲基D-天冬氨酸受体（NMDAR）介导的突触传递的贡献。在小鼠海马切片和人神经元细胞中，SV处理增加了NMDAR的GluN 2B亚基的表面分布，而不影响细胞胆固醇含量。我们的结论是，SV诱导的海马突触可塑性增强可能是介导的突触NMDAR组件，主要负责驱动CA 1区的突触可塑性增强。
The ramifications of statins on plasma cholesterol and coronary heart disease have been well documented. However, there is increasing evidence that inhibition of the mevalonate pathway may provide independent neuroprotective and procognitive pleiotropic effects, most likely via inhibition of isoprenoids, mainly farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP). FPP and GGPP are the major donors of prenyl groups for protein prenylation. Modulation of isoprenoid availability impacts a slew of cellular processes including synaptic plasticity in the hippocampus. Our previous work has demonstrated that simvastatin (SV) administration improves hippocampusdependent spatial memory, rescuing memory deficits in a mouse model of Alzheimer’s disease. Treatment of hippocampal slices with SV enhances long-term potentiation (LTP), and this effect is dependent on the activation of Akt (protein kinase B). Further studies showed that SV-induced enhancement of hippocampal LTP is driven by depletion of FPP and inhibition of farnesylation. In the present study, we report the functional consequences of exposure to SV at cellular/synaptic and molecular levels. While application of SV has no effect on intrinsic membrane properties of CA1 pyramidal neurons, including hyperpolarization-activated cyclic-nucleotide channel-mediated sag potentials, the afterhyperpolarization (AHP), and excitability, SV application potentiates the N-methyl D-aspartate receptor (NMDAR)-mediated contribution to synaptic transmission. In mouse hippocampal slices and human neuronal cells, SV treatment increases the surface distribution of the GluN2B subunit of the NMDAR without affecting cellular cholesterol content. We conclude that SV-induced enhancement of synaptic plasticity in the hippocampus is likely mediated by augmentation of synaptic NMDAR components that are largely responsible for driving synaptic plasticity in the CA1 region.
登录
查看更多内容
影响因子：
2.9
作者：
Lapchak, Paul A.;Han, Moon Ku
通讯作者：
Han, Moon Ku
影响因子：
168.9
作者：
Jick, H;Zornberg, GL;Drachman, DA
通讯作者：
Drachman, DA
影响因子：
56.9
作者：
BROWN, MS;GOLDSTEIN, JL
通讯作者：
GOLDSTEIN, JL
DOI：
10.1523/jneurosci.4144-09.2009
发表时间：
2009-10-28
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Ghosh A;Roy A;Matras J;Brahmachari S;Gendelman HE;Pahan K
通讯作者：
Pahan K
影响因子：
39.2
作者：
KANNEL, WB;CASTELLI, WP;MCNAMARA, PM
通讯作者：
MCNAMARA, PM