低频重复经颅磁刺激对BTBR T^(+)Itpr3^(tf)/J小鼠孤独症样行为的影响

Effect of low-frequency repetitive transcranial magnetic stimulation on autism-like behavior in BTBR T^(+)Itpr3^(tf)/J mice

目的探讨低频重复经颅磁刺激(repetitive transcranial magnetic stimulation,rTMS)对BTBR T+Itpr3tf/J(BTBR)孤独症谱系障碍(autism spectrum disorder,ASD)模型鼠的作用及可能机制。方法 雄性BTBR小鼠和雄性B6小鼠分别随机分配到孤独症模型+1 Hz rTMS治疗组(BTBR+1 Hz组)、BTBR组、B6+1 Hz组、对照组(B6组),每组7只。6周大开始对BTBR+1 Hz组及B6+1 Hz组进行rTMS,对BTBR组及B6组进行假刺激,治疗周期(共12 d)结束次日起进行三箱社交、理毛、埋珠、旷场、悬尾及强迫游泳实验。酶联免疫吸附试验(enzyme linked immunosorbent assay,ELISA)检测小鼠脑皮质及海马中白介素-1β(interleukin-1β,IL-1β)、白介素-6(interleukin-6,IL-6)、白介素-18(interleukin-18,IL-18)、白介素-23(interleukin-23,IL-23)、肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)和干扰素-γ(interferon-γ,IFN-γ)水平。结果 BTBR组社交时间少,理毛时间及皮质IL-1β、IL-18、TNF-α和海马IL-1β、IL-6、IL-18、TNF-α、IFN-γ较B6组有统计学差异(P<0.05)。rTMS治疗后,BTBR+1 Hz组小鼠在三箱社交实验中社交偏好测试和社交新奇偏好测试处在陌生小鼠侧室时间比新物体[(237.60±40.80) s vs.(184.10±23.94) s, P=0.019]或熟悉小鼠[(196.80±61.17) s vs.(260.50±48.59) s, P=0.013]侧室时间更长,BTBR+1 Hz组与BTBR组相比,理毛实验中的理毛时间缩短[(33.35±7.74) s vs.(81.95±38.71) s, P=0.001],皮质IL-1β、IL-18和TNF-α降低(P<0.05),以及海马IL-1β、IL-6、IL-18、TNF-α和IFN-γ降低(P<0.05)。此外,所有BTBR小鼠埋珠数量较B6小鼠增多(P<0.01),1 Hz rTMS可以显著降低小鼠皮质IL-23、IFN-γ及海马IL-23水平(P<0.05)。结论 1 Hz rTMS可以改善BTBR小鼠的社交缺陷,减少刻板行为;其作用可能是通过降低皮质及海马异常增高的炎症反应实现的。

Objective To investigate the effect of low-frequency repetitive transcranial magnetic stimulation(rTMS)on the BTBR mice,one of the idiopathic autism spectrum disorder mouse models.Method Male BTBR and B6 mice were randomly assigned to the BTBR+1 Hz group,BTBR group,B6+1 Hz group,and B6 group.At six weeks of age,1 Hz rTMS treatment was administered to the BTBR+1 Hz and B6+1 Hz groups and false stimulation treatment was administered to the BTBR and B6 groups at the same time.Behavioral tests were conducted to test sociability,repetitive behaviors,locomotion,anxiety,and depression,after which IL-1β,IL-6,IL-18,IL-23,TNF-α,and IFN-γin the cortex and hippocampus were measured.Result The mice in the BTBR group had a shorter social duration.Compared to the mice in the B6 group,there were significant differences in self-grooming duration,the levels of IL-1β,IL-18,and TNF-αin the cortex and IL-1β,IL-6,IL-18,TNF-α,and IFN-γin the hippocampus of the mice in the BTBR group(P<0.05).After treatment with rTMS,the three-chambered social approach task showed that the mice in the BTBR+1 Hz group had a longer time in sociability recognition[(237.60±40.80)s vs.(184.10±23.94)s,P=0.019]and social novelty recognition stage[(196.80±61.17)s vs.(260.50±48.59)s,P=0.013].In the self-grooming test,the mice in the BTBR+1 Hz group had a shorter grooming time than the mice in the BTBR group[(33.35±7.74)s vs.(81.95±38.71)s,P=0.001].The levels of IL-1β,IL-18 and TNF-α(P<0.05)in the cortex and IL-1β,IL-6,IL-18,TNF-αand IFN-γ(P<0.05)in the hippocampus of the mice in the BTBR+1 Hz group were significantly reduced compared with the mice in the BTBR group.In addition,the BTBR mice buried more marbles than the B6 mice(P<0.01),and 1 Hz rTMS could significantly reduce the level of IL-23 and IFN-γin the cortex(P<0.05)and the level of IL-23 in the hippocampus(P<0.05).Conclusion 1 Hz rTMS improves social deficits and reduces repetitive behavior in BTBR mice.These effects may be associated with the reduction in elevated neuroinflammatory response in the cortex and hippocampus.