GSK3抑制剂氯化锂对脆性X综合征模型小鼠避暗行为的干预作用

Theraputic effects of lithium chloride on passive avoidance behavior in a mouse model of Fragile X Syndrome

目的探讨糖原合成酶激酶3(glycogen synthase kinase3,GSK3)抑制剂氯化锂对脆性X综合症小鼠模型的避暗行为的干预作用及机制。方法通过对30日龄脆性X综合症小鼠连续腹腔注射不同剂量氯化锂5 d,用药第4天和第5天进行避暗实验;同时用免疫印迹技术检测Fmr1 knockout(KO)及wild type(WT)小鼠的海马和皮层总GSK 3β和磷酸化GSK 3β(P-GSK3β)的变化。结果在避暗实验中,KO鼠与WT鼠,两者潜伏期及错误次数分别为(56±32)s,(83±24)s;(7±3)次,(3±2)次;免疫印迹实验结果:KO鼠皮层及海马P-GSK3β表达平均灰度值分别为69,63;WT鼠皮层和海马均为100。注射氯化锂后,KO鼠和WT鼠总GSK3β无明显改变,而KO鼠60 mg/kg,120 mg/kg,200 mg/kg组皮层P-GSK3β表达平均灰度值分别为:147,151,234;海马P-GSK3β分别为108,111,146,较空白组增多;P<0.05。WT鼠用氯化锂后,潜伏期和错误次数以及P-GSK3β表达变化无统计学意义。结论氯化锂能改善KO鼠的学习记忆能力,可能与氯化锂导致的P-GSK3β的表达增加有关,对脆性X综合征基因敲除小鼠有治疗作用。

Objective To study the theraputic effects of lithium chloride on step-through behaviors and the activity of Glycogen Synthase Kinase 3β （GSK3β） in Fragile X Syndrome in mice. Methods Thirty-day-oht wild- type （WT） or Fmrl KO littermates received either normal saline or different doses of lithium chloride （30 mg/kg, 60 mg/kg, 90 mg/kg, 120 mg/kg or 200 mg/kg） for five consecutive days. Step-through testing was used to detect the latency period and error c, ount at 4 and 5 days following lithium treatment. Meanwhile, Western blot was used to ex- amine the expression of GSK3β and Phosphorylated GSK3β（P-GSK3β,） in mouse hippocampus and cortex. Results Compared with non-treated WT mice, non-treated KO mice had shorter latency period and more error counts in pas- sive avoidanee tests, suggesting that KO mice had learning and memory impairments. The expression level of phos- phoc,lated P-GSK3β） was lower in Fmrl KO than in WT mice. Lithium treatment could ceover the learning and memory impairments and increase the expression level of P-GSK3. Conclusions Lithium ameliorates passive avoid- ance impairment probably through increasing the expression of P-GSK3βin the Fmrl knockout mice.