pSynGAP1在脂多糖诱发脓毒症小鼠远期认知障碍中的作用

The role of pSynGAP1 in LPS induced-long-term neurobehavioral abnormities

目的尽管目前通过对单个基因或蛋白质的研究已经揭示了炎症引发神经行为异常的各种机制,但尚缺乏对海马蛋白组学进行系统分析。文中探讨pSynGAP1在脂多糖(LPS)诱发脓毒症小鼠远期认知障碍中的作用。方法选取3~4月龄雄性C57BL/6小鼠105只,并按照随机数字表法分为等渗盐水组(对照组,n=25)、LPS组(n=40)与LPS+Roscovitine(LPS+R组,n=40)。对照组小鼠腹腔注射等渗盐水(10 mL/kg);LPS组小鼠腹腔注射LPS(5 mg/kg);LPS+R组小鼠腹腔注射LPS(5 mg/kg)。各组小鼠注射完成后饲养12个月。对照组及LPS组小鼠在行为学检测完成后取海马组织,采用iTRAQ技术寻找发挥重要作用的蛋白靶点。采用Western blot法检测海马组织中SynGAP1和pSynGAP1的表达变化。自行为学检测前3 d起,LPS+R组每天腹腔注射Roscovitine(20 mg/kg);对照组和LPS组每天腹腔注射等量等渗盐水。采用Western blot法检测海马组织中、pSynGAP1表达变化。在体电生理记录海马CA1区场电位。结果与对照组小鼠相比,LPS组pSynGAP1表达水平显著降低(P<0.05);同时CA1区神经网络振荡中θ和γ振荡功率显著降低(P<0.05)。与LPS组小鼠相比,LPS+R组pSynGAP1表达水平显著增加(P<0.05);与LPS组小鼠相比,LPS+R组CA1区神经网络振荡中θ和γ振荡功率显著增加(P<0.05);Roscovitine干预可显著上调pSynGAP1的表达水平,逆转其神经网络振荡异常,并改善相关行为学的表现。结论pSynGAP1介导的海马振荡网络紊乱在LPS诱导的神经行为异常中发挥关键重要作用,可作为全身炎症相关性疾病潜在治疗靶点。

Objective To explore the role of pSynGAP1 in lipopolysaccharide(LPS)induced-long-term neurobehavioral abnormities.Methods A total of 105 male C57BL/6 mice(3-4 months)were randomly divided into three groups:control group(n=25),LPS(n=40)or LPS+Roscovitine(LPS+R)group(n=40).Animals in the control group were received normal saline(10 ml/kg).Animals in LPS group were received LPS injection(5 mg/kg),in LPS+R group received LPS injection(5 mg/kg).All mice were fed for 12 months.After the control group and LPS behavioral tests is completed,the hippocampal tissue was taken and iTRAQ technology was used to find the important protein target.The expression of syngap1 and psyngap1 in hippocampus was detected by Western blot.LPS+R group was followed by Roscovitine injections 3 days before cognitive tests until the end of the behavioral test.The control group and LPS group were given the same amount of normal saline.Western blot was used to detect the expression of pCamkII and psynGAP1 in hippocampus.Local field potential was recorded in the hippocampal CA1.Results By the protein-protein interaction networks,we found that SynGAP1 was among the hub of synaptic plasticity.Compared with control group,pSynGAP1 expression was significantly decreased in LPS group(P<0.05),which was accompanied by decreases in theta and gamma oscillations in the hippocampus.Roscovitine treatment reversed the decreased pSynGAP1 expression,theta,and gamma oscillations,which ultimately improved the behavioral performances.Conclusion pSynGAP1 mediated-disturbance in hippocampal network plays a key role LPS-induced cognitive impairment,which may serve as a therapeutic target for inflammation-related disorders.