Qin Mei, Zeidler Zachary, Moulton Kristen, Krych Leland, Xia Zengyan, Smith Carolyn B
Section on Neuroadaptation and Protein Metabolism, National Institute of Mental Health, National Institutes of Health, 10 Center Drive, Bldg. 10, Rm. 2D54, Bethesda, MD 20892, USA.
Section on Neuroadaptation and Protein Metabolism, National Institute of Mental Health, National Institutes of Health, 10 Center Drive, Bldg. 10, Rm. 2D54, Bethesda, MD 20892, USA.
Behav Brain Res. 2015 Sep 15;291:164-171. doi: 10.1016/j.bbr.2015.05.003. Epub 2015 May 12.
Silencing the gene FMR1 in fragile X syndrome (FXS) with consequent loss of its protein product, FMRP, results in intellectual disability, hyperactivity, anxiety, seizure disorders, and autism-like behavior. In a mouse model (Fmr1 knockout (KO)) of FXS, a deficit in performance on the passive avoidance test of learning and memory is a robust phenotype. We report that drugs acting on the endocannabinoid (eCB) system can improve performance on this test. We present three lines of evidence: (1) Propofol (reported to inhibit fatty acid amide hydrolase (FAAH) activity) administered 30 min after training on the passive avoidance test improved performance in Fmr1 KO mice but had no effect on wild type (WT). FAAH catalyzes the metabolism of the eCB, anandamide, so its inhibition should result in increased anandamide levels. (2) The effect of propofol was blocked by prior administration of the cannabinoid receptor 1 antagonist AM-251. (3) Treatment with the FAAH inhibitor, URB-597, administered 30 min after training on the passive avoidance test also improved performance in Fmr1 KO mice but had no effect on WT. Our results indicate that the eCB system is involved in FXS and suggest that the eCB system is a promising target for treatment of FXS.
在脆性X综合征（FXS）中，基因FMR1沉默并随之失去其蛋白质产物FMRP，会导致智力残疾、多动、焦虑、癫痫症和自闭症样行为。在FXS的小鼠模型（Fmr1基因敲除（KO））中，学习和记忆的被动回避测试表现存在缺陷是一种显著的表型。我们报告称，作用于内源性大麻素（eCB）系统的药物可以改善该测试中的表现。我们提供了三条证据：（1）在被动回避测试训练后30分钟给予丙泊酚（据报道可抑制脂肪酸酰胺水解酶（FAAH）活性），可改善Fmr1基因敲除小鼠的表现，但对野生型（WT）小鼠没有影响。FAAH催化eCB花生四烯乙醇胺的代谢，因此其抑制作用应会导致花生四烯乙醇胺水平升高。（2）预先给予大麻素受体1拮抗剂AM - 251可阻断丙泊酚的作用。（3）在被动回避测试训练后30分钟给予FAAH抑制剂URB - 597进行治疗，也可改善Fmr1基因敲除小鼠的表现，但对野生型小鼠没有影响。我们的结果表明，eCB系统与FXS有关，并提示eCB系统是治疗FXS的一个有前景的靶点。
