脆弱拟杆菌BF839可改善Fmr1 KO小鼠的学习记忆能力及社交新奇偏好能力

Bacteroides fragilis BF839 can improve learning,memory and social novelty of fragile X-mental retardation gene 1 knockout mice

目的观察脆弱拟杆菌BF839干预对脆性X智力低下基因1(Fmr1)敲除(Fmr1 KO)小鼠学习记忆能力及社交新奇偏好能力的影响。方法将3周龄30只FVB系Fmr1 KO小鼠按随机数字表法分为Fmr1 KO组(n=15)和Fmr1 KO+BF839组(n=15),Fmr1 KO组小鼠每天自由饮用高压灭菌自来水,Fmr1 KO+BF839组小鼠每天饮用BF839菌液(10 mL/d)。另取11只每天自由饮用高压灭菌自来水的野生型(WT)小鼠作为对照(WT组)。干预4周后,采用Morris水迷宫实验观察各组小鼠间逃避潜伏期、穿越原平台次数的差异,采用三箱社交实验观察各组小鼠间与陌生小鼠接触次数、接触时间的差异。结果Fmr1 KO组小鼠第4天的逃避潜伏期[(46.06±10.29)s]明显高于WT组[(33.39±12.02)s],Fmr1 KO+BF839组小鼠第4天的逃避潜伏期[(28.39±9.07)s]明显低于Fmr1 KO组,差异均有统计学意义(P<0.05);Fmr1 KO+BF839组小鼠第4天的逃避潜伏期略低于WT组,差异无统计学意义(P>0.05)。Fmr1 KO组小鼠穿越原平台次数[0.00(0.00,1.00)次]略低于WT组[1.00(0.00,1.00)次],差异无统计学意义(P>0.05);Fmr1 KO+BF839组小鼠穿越原平台次数[1.50(1.00,2.00)次]明显高于Fmr1 KO组及WT组,差异均有统计学意义(P<0.05)。Fmr1 KO组小鼠与陌生小鼠的接触次数[5.50(0.50,12.75)次]少于WT组[7.00(4.00,17.00)次],但差异无统计学意义(P>0.05);Fmr1 KO+BF839组小鼠与陌生小鼠的接触次数[23.00(16.00,36.00)次]明显多于Fmr1 KO组及WT组,差异均有统计学意义(P<0.05)。Fmr1 KO组小鼠与陌生小鼠的接触时间[9.50(0.50,41.95)s]明显少于WT组[142.00(65.00,171.60)s],差异有统计学意义(P<0.05);Fmr1 KO+BF839组小鼠与陌生小鼠的接触时间[69.60(50.40,98.40)s]明显多于Fmr1 KO组,差异有统计学意义(P<0.05);Fmr1 KO+BF839组小鼠与陌生小鼠的接触时间少于WT组,但差异无统计学意义(P>0.05)。结论BF839早期干预能明显提高Fmr1 KO小鼠的学习记忆能力及社交新奇偏好能力,甚至使Fmr1 KO小鼠恢复至正常水平,提示BF839有可能成为治疗脆性X综合征及孤独症的新工具。

Objective To observe the effect of bacteroides fragilis BF839 intervention on learning,memory and social novelty of fragile X-mental retardation gene 1(Fmr1)knockout(KO)mice.Methods Thirty three-week-old Fmr1 KO mice were randomly divided into Fmr1 KO group(n=15)and Fmr1 KO+BF839 group(n=15).Mice in the Fmr1 KO group freely drank autoclaved tap water everyday;mice in the Fmr1 KO+BF839 group drank BF839 bacterial liquid(10 mL/d)everyday;11 wild-type mice freely drank autoclaved tap water everyday were set as controls(WT group).After 4 weeks of intervention,Morris water maze test was used to observe the differences in escape latency and frequencies of crossing the original platform among mice in each group;Three-chamber Social Interaction Test was used to observe the differences in contact frequencies and contact durations with unfamiliar mice among mice in each group.Results On the 4th d of experiment,the escape latency of mice in the Fmr1 KO group([46.06±10.29]s)was significantly longer than that in the WT group([33.39±12.02]s,P<0.05);the escape latency of mice in the Fmr1 KO+BF839 group([28.39±9.07]s)was significantly shorter than that in the Fmr1 KO group(P<0.05);the escape latency of mice in the Fmr1 KO+BF839 group was slightly shorter than that in the WT group without significant difference(P>0.05).The frequencies of crossing through the original platform of mice in Fmr1 KO group(0.00[0.00,1.00]time)was slightly less than that in WT group(1.00[0.00,1.00]time)without significant difference(P>0.05);that in the Fmr1 KO+BF839 group(1.50[1.00,2.00]times)was significantly larger than that in the Fmr1 KO group and WT group(P<0.05).The contact frequencies of the mice in the Fmr1 KO group with unfamiliar mice(5.50[0.50,12.75]times)was less than that in the WT group(7.00[4.00,17.00]times)without significant difference(P>0.05);that in the Fmr1 KO+BF839 group(23.00[16.00,36.00]times)was significantly increased as compared with that in the Fmr1 KO group and WT group(P<0.05).The contact duration of mice in the Fmr1 KO group with unfamiliar mice(9.50[0.50,41.95]s)was significantly shorter than that in the WT group(142.00[65.00,171.60]s,P<0.05);Fmr1 KO+BF839 group had significantly longer contact duration with unfamiliar mice(69.60[50.40,98.40]s)than Fmr1 KO group(P<0.05);the contact duration of mice in Fmr1 KO+BF839 group with unfamiliar mice was shorter than that in WT group without significant difference(P>0.05).Conclusion Early BF839 intervention can significantly improve the learning,memory abilities and social novelty of Fmr1 KO mice,and even restore the Fmr1 KO mice to normal levels,which suggests that BF839 may become a new tool for treatment of fragile X syndrome and autism.