LY395756, an mGluR2 agonist and mGluR3 antagonist, enhances NMDA receptor expression and function in the normal adult rat prefrontal cortex, but fails to improve working memory and reverse MK801-induced working memory impairment.
LY395756, an mGluR2 agonist and mGluR3 antagonist, enhances NMDA receptor expression and function in the normal adult rat prefrontal cortex, but fails to improve working memory and reverse MK801-induced working memory impairment.
复制标题
LY395756 是一种 mGluR2 激动剂和 mGluR3 拮抗剂，可增强正常成年大鼠前额皮质中 NMDA 受体的表达和功能，但无法改善工作记忆并逆转 MK801 诱导的工作记忆损伤
DOI：
10.1016/j.expneurol.2015.08.019
复制
发表时间：
2015-11
影响因子：
5.3
通讯作者：
Gao WJ
中科院分区：
文献类型：
--
作者：
Li ML;Yang SS;Xing B;Ferguson BR;Gulchina Y;Li YC;Li F;Hu XQ;Gao WJ
已经提出靶向II组代谢型谷氨酸受体（mGluR 2/3）来纠正功能失调的谷氨酸能系统，特别是NMDA受体（NMDAR）功能减退，用于治疗精神分裂症。然而，mGluR 2/3的激活如何影响成年动物的NMDAR功能仍然难以捉摸。在这里，我们显示了LY 395756（LY 39），一种化合物作为mGluR 2激动剂和mGluR 3拮抗剂，对正常成年大鼠前额叶皮层（PFC）的NMDAR表达和功能以及精神分裂症MK 801模型中的工作记忆功能的影响。我们发现，在体内给药LY 39显着增加NMDAR亚基和NR 2B磷酸化的PFC中的总蛋白水平，沿着的振幅NMDAR介导的微型兴奋性突触后电流（mEPSC）在前额叶皮层神经元。此外，LY 39还显著增加mTOR和pmTOR表达，但不增加ERK 1/2、Akt和GSK 3 β，表明mTOR信号传导被激活。事实上，mTOR抑制剂雷帕霉素和转录抑制剂放线菌素D阻断了LY 39对NMDAR-mEPSC的增强作用。这些结果表明，LY 39通过未鉴定的mTOR介导的蛋白质合成调节正常成年大鼠PFC中NMDAR的表达和功能。然而，这种变化不足以影响正常动物的工作记忆功能，也不足以逆转MK 801诱导的工作记忆缺陷。我们的数据提供了一种新的化合物，作为一个mGluR 2激动剂和mGluR 3拮抗剂突触NMDAR的表达和功能在成年大鼠PFC的体内效果的第一个证据，虽然其对PFC依赖的认知功能的影响仍有待探讨。
Targeting group II metabotropic glutamate receptors (mGluR2/3) has been proposed to correct the dysfunctional glutamatergic system, particularly NMDA receptor (NMDAR) hypofunction, for treatment of schizophrenia. However, how activation of mGluR2/3 affects NMDAR function in adult animals remains elusive. Here we show the effects of LY395756 (LY39), a compound acting as both an mGluR2 agonist and mGluR3 antagonist, on the NMDAR expression and function of normal adult rat prefrontal cortex (PFC) as well as working memory function in the MK801 model of schizophrenia. We found that in vivo administration of LY39 significantly increased the total protein levels of NMDAR subunits and NR2B phosphorylation in the PFC, along with the amplitude of NMDAR-mediated miniature excitatory postsynaptic currents (mEPSC) in the prefrontal cortical neurons. Moreover, LY39 also significantly increased mTOR and pmTOR expression, but not ERK1/2, Akt, and GSK3β, suggesting an activation of mTOR signaling. Indeed, the mTOR inhibitor rapamycin, and actinomycin-D, a transcription inhibitor, blocked the enhanced effects of LY39 on NMDAR-mEPSCs. These results indicate that LY39 regulates NMDAR expression and function through unidentified mTOR-mediated protein synthesis in the normal adult rat PFC. However, this change is insufficient to affect working memory function in normal animals, nor to reverse the MK801-induced working memory deficit. Our data provide the first evidence of an in vivo effect of a novel compound that acts as both an mGluR2 agonist and mGluR3 antagonist on synaptic NMDAR expression and function in the adult rat PFC, although its effect on PFC-dependent cognitive function remains to be explored.