新生期暴露MK-801对成年雌性大鼠再认记忆和海马兴奋-抑制平衡的影响

摘要

目的 探讨新生期亚慢性注射谷氨酸N-甲基-D-天冬氨酸(N-methyl-D-aspartate,NMDA)受体拮抗剂-地卓西平马来酸盐(dizocilpine maleate,MK-801)对成年期雌性大鼠再认记忆以及海马突触水平上兴奋-抑制平衡的影响.方法 (1)新生雌性大鼠随机分为MK-801模型组和对照组,在出生后(postnatal day,PND)第5～14天皮下注射MK-801(0.25 mg/kg,2次/d)或生理盐水.(2)在成年期(PND 73-75)进行线索物体辨别测试.(3)用免疫组织化学染色法检测海马囊泡性谷氨酸转运体1(vesicular glutamate transporter 1,VGLUT1)与囊泡GABA转运体(vesicular GABA transporter,VGAT)的表达水平.结果 (1)MK-801组的大鼠对新物体的偏好指数与对照组相比显著降低(t=-2.762,P=0.012);(2) MK-801组大鼠海马各亚区内VGLUT1表达水平未发生显著改变(P＞0.05),VGAT在CA1区的表达量(39.60± 2.19)与对照组(48.19±2.10)相比显著降低(P＜0.05),CA1区VGLUT1/VGAT的比值(1.16±0.05)、CA3区VGLUT1/VGAT的比值(1.44±0.03)与对照组[CA1区:(0.99±0.05),CA3区:(1.28±0.02)]相比显著升高(均P＜0.05).结论 脑发育关键期阻断NMDA受体,对雌性大鼠的联结再认记忆和海马的兴奋-抑制平衡产生了远期的破坏作用,后者可能是认知功能改变的机制之一.%Objective To investigate the long-term effects of repeated neonatal administration of dizocipline maleate (MK-801),the glutamate N-methyl-D-aspartate (NMDA) receptor antagonist,on recognition memory and hippocampal excitatory-inhibitory balance at the synaptic level in adult female rats.Methods Neonatal female Sprague-Dawley (SD) rats were randomly divided into model group and control group.Rats were administrated subcutaneously with MK-801 or normal saline from postnatal day (PND) 5 to PND14 (0.25 mg/kg,twice daily).(1) Object-in-context recognition test was performed on PND73-75.(2)The expression levels of vesicular glutamate transporter 1 (VGLUT1) and vesicular GABA transporter (VGAT) in hippocampus were detected by immunohistochemical staining.Results (1) The preference index of model group for new objects was significantly lower than that of the control group (t =-2.762,P=0.012).(2) There was no significant difference in the expression of VGLUT1 in hippocampus of MK-801 mode group(P＞0.05).Compared with control group(48.19±2.10),the VGAT level of model group in CA1 (39.60±2.19) was lower.Compared with control group (CA1:(0.99±0.05),CA3:(1.28±0.02),the ratio of VGLUT1/VGAT was significantly upregulated in CA1(1.16±0.05) and CA3(1.44±0.03) (P＜0.05).Conclusion Early NMDA receptor inhibition produces long-term deleterious effects on associative recognition memory and excitatory-inhibitory balance of hippocampus in female rats.These biochemical abnormalities may contribute to cognitive impairments observed in this study.