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首页> 外文期刊>Neuropharmacology >Therapeutic significance of NR2B-containing NMDA receptors and mGluR5 metabotropic glutamate receptors in mediating the synaptotoxic effects of beta-amyloid oligomers on long-term potentiation (LTP) in murine hippocampal slices.
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Therapeutic significance of NR2B-containing NMDA receptors and mGluR5 metabotropic glutamate receptors in mediating the synaptotoxic effects of beta-amyloid oligomers on long-term potentiation (LTP) in murine hippocampal slices.

机译：含NR2B的NMDA受体和mGluR5代谢型谷氨酸受体在介导β-淀粉样低聚物对小鼠海马切片的长期增强（LTP）的突触毒性作用中的治疗意义。

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Soluble amyloid beta (Abeta) oligomers are widely accepted to be neurotoxic and lead to the memory loss and neuronal death observed in Alzheimer's disease (AD). Ample evidence suggests that impairment in glutamatergic signalling is associated with AD pathology. In particular, Abeta(1-42) is thought to affect N-methyl-d-aspartate (NMDA) receptor function and abolish the induction of long-term potentiation (LTP), which is regarded to be a phenomenon relevant to memory formation. The involvement of glutamatergic signalling in the pathology of AD is underscored by the therapeutic success of memantine, an uncompetitive NMDA receptor antagonist, used to treat patients with moderate to severe AD. In this study we show that Abeta(1-42) oligomers applied to acute murine hippocampal slices prevented, in a concentration-dependent manner, the development of CA1-LTP after tetanic stimulation of the Schaffer collaterals with a half maximal inhibitory concentration of around 2 nM (before oligomerization). The highest concentration of Abeta(1-42) oligomers (50 nM before oligomerization) completely blocked LTP (105 +/- 1% potentiation versus 141 +/- 3% in control) whereas scrambled Abeta(1-42) (50 nM) was without effect (144 +/- 10% potentiation). Pre-incubation with memantine (1 muM) restored LTP in the presence of Abeta(1-42) (50 nM; 135 +/- 5% potentiation). NMDA receptors containing the NR2B subunit have been proposed to play a particularly important role in excitotoxicity, functioning as extracellular "death receptors". The metabotropic glutamate receptor 5 (mGluR5) is mechanistically coupled to postsynaptic NMDA receptors. As such, allosteric sites on both receptors offer alternative means to modulate NMDA receptor function. We therefore tested low concentrations (each 300 nM) of allosteric antagonists of NR2B (Ro 25-6981, [R-(R *,S *)]-alpha-(4-Hydroxyphenyl)-beta-methyl-4(phenylmethyl)-1-piperidine propanol hydrochloride) and mGluR5 receptors (MPEP, 2-methyl-6-(phenylethynyl)-pyridine). Both compounds restored LTP in the presence of Abeta(1-42) oligomers (50 nM, fEPSPs were potentiated to 129 +/- 13% and 133 +/- 7% respectively). Finally, we demonstrated that slices from mice heterozygous for NR2B receptor) in the forebrain are not susceptible to the toxic effects of Abeta(1-42) oligomers but express normal LTP (138 +/- 6%). These experiments demonstrate that glutamate receptor antagonists delivered at concentrations which still allow physiological activities in vitro, are able to prevent Abeta(1-42) oligomer-induced synaptic toxicity and further support the glutamatergic system as a target for the development of improved symptomaticeuroprotective treatments for AD.
机译：可溶性淀粉样β（Abeta）低聚物被广泛接受为具有神经毒性，并导致在阿尔茨海默氏病（AD）中观察到的记忆力丧失和神经元死亡。大量证据表明，谷氨酸能信号传导障碍与AD病理相关。特别是，Abeta（1-42）被认为会影响N-甲基-d-天门冬氨酸（NMDA）受体功能，并取消了对长时程增强（LTP）的诱导，后者被认为与记忆形成有关。美金刚是一种无竞争性的NMDA受体拮抗剂，用于治疗中度至重度AD患者，突显出谷氨酸能信号参与AD的病理。在这项研究中，我们显示了Abeta（1-42）低聚物应用于急性小鼠海马切片，以浓度依赖的方式阻止了强力刺激Schaffer侧支后半数抑制浓度约为2的CA1-LTP的发展。 nM（低聚之前）。最高浓度的Abeta（1-42）低聚物（低聚前为50 nM）完全阻断了LTP（增强电位为105 +/- 1％，而对照组为141 +/- 3％），而扰乱的Abeta（1-42）（50 nM）没有效果（144 +/- 10％增强）。在Abeta（1-42）（50 nM; 135 +/- 5％增强）的存在下，与美金刚（1μM）预温育可恢复LTP。已经提出了含有NR2B亚基的NMDA受体在兴奋性毒性中起着特别重要的作用，起着细胞外“死亡受体”的作用。代谢型谷氨酸受体5（mGluR5）机械耦合到突触后NMDA受体。这样，两种受体上的别构位点提供了调节NMDA受体功能的替代手段。因此，我们测试了NR2B（Ro 25-6981，[R-（R *，S *）]-α-（4-羟基苯基）-β-甲基-4（苯基甲基）- 1-哌啶丙醇盐酸盐）和mGluR5受体（MPEP，2-甲基-6-（苯基乙炔基）-吡啶）。两种化合物均在Abeta（1-42）低聚物（50 nM，fEPSPs分别增强至129 +/- 13％和133 +/- 7％）的存在下恢复了LTP。最后，我们证明了来自前脑杂合的NR2B受体小鼠的切片对Abeta（1-42）低聚物的毒性作用不敏感，但表达正常的LTP（138 +/- 6％）。这些实验表明，谷氨酸受体拮抗剂的浓度仍能在体外提供生理活性，能够预防Abeta（1-42）低聚物诱导的突触毒性，并进一步支持谷氨酸能系统作为开发对症/神经保护药的目标AD的治疗。

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