State Key Lab of Reproductive Medicine, Nanjing Medical University, Nanjing 211166, China; Department of Physiology, Nanjing Medical University, Nanjing 211166, China.
Department of Physiology, Nanjing Medical University, Nanjing 211166, China.
Neuropharmacology. 2018 Sep 1;139:257-267. doi: 10.1016/j.neuropharm.2018.03.026. Epub 2018 Mar 22.
Statins by reducing farnesyl-pyrophosphate or farnesyl transferase inhibitors have been demonstrated to enhance spatial memory and long-term potentiation (LTP). The objective of this study was to investigate effects of the synthetic Ras inhibitor S-trans, trans-farnesylthiosalicylic acid (FTS) on spatial cognitive function in adult mice, synaptic plasticity in hippocampal CA1 regions, and NMDA receptor (NMDAr) activity of pyramidal cells. Here, we show that administering FTS (5 mg/kg, i.p.) enhanced spatial cognitive performance, as assessed via Morris water maze and Y-maze tests. Treating hippocampal slices with FTS (5 μM) for 2 h enhanced selectively NMDAr-dependent LTP without changing the synaptic properties. In comparison with the controls, the FTS-treated slices showed increases in the amplitude of NMDA-evoked currents (I) and the phosphorylation of NMDAr GluN2A/GluN2B subunits and Src. The Src inhibitor PP2 blocked the enhancing effects of FTS on the activity and phosphorylation of NMDAr. In FTS-treated slices, basal levels of CaMKII, ERK2 and CREB phosphorylation did not differ significantly from those of controls; however, high-frequency stimulation-induced increases in CaMKII, ERK2 and CREB phosphorylation were more significant than in the controls, which were sensitive to PP2 and NMDAr antagonist MK801. Furthermore, the phosphorylation of AMPA receptor GluR1 during LTP was higher in FTS-treated slices compared with the control, which depended on Src and ERK1/2 signaling. The results indicate that the Ras inhibition by FTS can enhance NMDAr-dependent LTP by increasing Src activity to promote NMDAr GluN2A/GluN2B phosphorylation, which then leads to spatial memory potentiation.
通过减少法呢基焦磷酸或法尼基转移酶抑制剂，他汀类药物已被证明可以增强空间记忆和长时程增强（LTP）。本研究的目的是研究合成 Ras 抑制剂 S-反式，反式-法尼基硫代水杨酸（FTS）对成年小鼠空间认知功能、海马 CA1 区突触可塑性和 NMDA 受体（NMDAr）活性的影响。在这里，我们表明，给予 FTS（5mg/kg，ip）可通过 Morris 水迷宫和 Y 迷宫测试增强空间认知表现。用 FTS（5μM）处理海马切片 2 小时可选择性增强 NMDAr 依赖性 LTP，而不改变突触特性。与对照组相比，FTS 处理的切片显示 NMDA 诱发电流（I）幅度增加，NMDAr GluN2A/GluN2B 亚基和Src 的磷酸化增加。Src 抑制剂 PP2 阻断了 FTS 对 NMDAr 活性和磷酸化的增强作用。在 FTS 处理的切片中，基础 CaMKII、ERK2 和 CREB 磷酸化水平与对照组无显著差异；然而，高频刺激诱导的 CaMKII、ERK2 和 CREB 磷酸化增加比对照组更显著，这对 PP2 和 NMDAr 拮抗剂 MK801 敏感。此外，与对照组相比，FTS 处理的切片中 LTP 期间 AMPA 受体 GluR1 的磷酸化更高，这依赖于 Src 和 ERK1/2 信号。结果表明，FTS 通过增加 Src 活性来增强 NMDAr 依赖性 LTP，从而促进 NMDAr GluN2A/GluN2B 磷酸化，从而增强空间记忆。
