Group I mGluR antagonist rescues the deficit of D1-induced LTP in a mouse model of fragile X syndrome.
Group I mGluR antagonist rescues the deficit of D1-induced LTP in a mouse model of fragile X syndrome.
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I 组 mGluR 拮抗剂可挽救脆性 X 综合征小鼠模型中 D1 诱导的 LTP 缺陷
DOI：
10.1186/1750-1326-7-24
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发表时间：
2012-05-28
影响因子：
15.1
通讯作者：
Zhao MG
中科院分区：
文献类型：
--
作者：
Xu ZH;Yang Q;Feng B;Liu SB;Zhang N;Xing JH;Li XQ;Wu YM;Gao GD;Zhao MG
背景脆性X综合征（Fragile X syndrome，FXS）是由Fmr 1基因编码的脆性X智力低下蛋白（Fragile X mental retardation protein，FMRP）的mRNA结合蛋白缺失引起的。第1组代谢型谷氨酸受体（Grp 1 mGluR）的过度活跃信号可能导致突触发育减慢和FXS的其他症状。我们的前期研究发现，在Fmr 1基因敲除（KO）小鼠中，D1受体对突触长时程增强（LTP）的易化作用受损。然而，Grp 1 mGluR的贡献，以促进突触可塑性D1受体刺激在前额叶cortex.ResultsHere，我们证明了DL-AP 3，一个Grp 1 mGluR拮抗剂，抢救LTP便利D1受体激动剂SKF 81297在Fmr 1 KO小鼠。在培养的Fmr 1 KO神经元中，Grp 1 mGluR抑制恢复了D1激活的GluR 1亚型AMPA受体表面插入。Grp 1 mGluR拮抗剂与D1激动剂同时处理可通过逆转G蛋白偶联受体激酶2（GRK 2）在Fmr 1 KO神经元的亚细胞再分布恢复D1受体信号。SKF 81297单独处理未能增加KO小鼠培养物中含NR 2B的N-甲基D-天冬氨酸受体（NMDAR）Tyr-1472（p-NR 2B-Tyr 1472）的磷酸化。然而，在KO小鼠的培养物中，DL-AP 3的同时处理可以通过SKF 81297拯救p-NR 2B-Tyr 1472的水平。行为学实验结果表明，Grp 1 mGluR拮抗剂与D1激动剂联合应用可抑制FXS小鼠的多动性，提高FXS小鼠的学习能力。结论Grp 1 mGluR拮抗剂与D1激动剂联合应用可有效抑制FXS小鼠的D1受体信号通路。
BackgroundFragile X syndrome (FXS) is caused by the absence of the mRNA-binding protein Fragile X mental retardation protein (FMRP), encoded by theFmr1gene. Overactive signaling by group 1 metabotropic glutamate receptor (Grp1 mGluR) could contribute to slowed synaptic development and other symptoms of FXS. Our previous study has identified that facilitation of synaptic long-term potentiation (LTP) by D1 receptor is impaired inFmr1knockout (KO) mice. However, the contribution of Grp1 mGluR to the facilitation of synaptic plasticity by D1 receptor stimulation in the prefrontal cortex has been less extensively studied.ResultsHere we demonstrated that DL-AP3, a Grp1 mGluR antagonist, rescued LTP facilitation by D1 receptor agonist SKF81297 inFmr1KO mice. Grp1 mGluR inhibition restored the GluR1-subtype AMPA receptors surface insertion by D1 activation in the culturedFmr1KO neurons. Simultaneous treatment of Grp1 mGluR antagonist with D1 agonist recovered the D1 receptor signaling by reversing the subcellular redistribution of G protein-coupled receptor kinase 2 (GRK2) in theFmr1KO neurons. Treatment of SKF81297 alone failed to increase the phosphorylation of NR2B-containing N-methyl D-aspartate receptors (NMDARs) at Tyr-1472 (p-NR2B-Tyr1472) in the cultures from KO mice. However, simultaneous treatment of DL-AP3 could rescue the level of p-NR2B-Tyr1472 by SKF81297 in the cultures from KO mice. Furthermore, behavioral tests indicated that simultaneous treatment of Grp1 mGluR antagonist with D1 agonist inhibited hyperactivity and improved the learning ability in theFmr1KO mice.ConclusionThe findings demonstrate that mGluR1 inhibition is a useful strategy to recover D1 receptor signaling in theFmr1KO mice, and combination of Grp1 mGluR antagonist and D1 agonist is a potential drug therapy for the FXS.
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影响因子：
56.9
作者：
Courtney, SM;Petit, L;Haxby, JV
通讯作者：
Haxby, JV
DOI：
10.1073/pnas.1013855108
发表时间：
2011-02-08
影响因子：
11.1
作者：
Krueger, Dilja D.;Osterweil, Emily K.;Bear, Mark F.
通讯作者：
Bear, Mark F.
影响因子：
64.5
作者：
Lee, FJS;Xue, S;Liu, F
通讯作者：
Liu, F
影响因子：
4.7
作者：
Gao, Can;Sun, Xiu;Wolf, Marina E.
通讯作者：
Wolf, Marina E.
影响因子：
5.3
作者：
Larson, J;Jessen, RE;du Hoffmann, J
通讯作者：
du Hoffmann, J