Objective To explore the alterations of ultrastructure of neuron and synapse in rat hippocampus induced by the expression changes of phospho cAMP response element-binding protein 1 (p-CREB1),and the effect of venlafaxine on the expression of p-CREB1 and relative neuronal and synaptic plasticity.Methods Fifty-four rats were randomly divided into 4 groups:normal group (n =12),depression model matched group (n =14),saline group (n =14),and venlafaxine medication group (n =14).Sucrose water consumption test and open field test were performed to observe the behavior of animals.To investigate the learning and memory ability,rats were tested by Morris water maze.The expression of p-CREB1 protein was detected by immunohistochemistry and the CREB1 mRNA was measured by RT-PCR.The ultrastructure of neuron and synapse were observed with electron microscope.Correlation analysis was used to measure the associations among the number of p-CREB1 positive cells,the parameters of Morris water maze and synaptic morphology.Results (1) The sucrose consumption in depression model matched group (7.4 ± 1.0) ml/100 g and saline group (7.5 ± 1.0) ml/100 g were significantly less than that in normal group (9.6 ± 0.3) ml/100 g and medication group (9.4 ± 0.8) ml/100 g,(F =17.851,P ＜ 0.01).Morris water maze showed that the escape latent period in depression model matched group (61.1 ± 10.5) s and saline group (59.0 ± 10.6) s were more than that in normal group (29.8 ± 10.1) s and medication group ((35.0 ± 8.5) s;F =30.559,P ＜ 0.01),which demonstrated the learning and memory ability of depression rats were decreased.(2) The positive cell number of p-CREB1 in the hippocampus of depression model matched group (21.07 ±5.99) and saline group (24.57 ±6.97) were lower than that in normal group (29.70 ± 6.21) and medication group (41.50 ± 11.95;F =16.497,P ＜ 0.01).(3) The CREB1 mRNA expression in the hippocampus of depression model matched group (0.58 ± 0.47) and saline group (0.45 ± 0.24) were less than that in normal group (1.03 ± 0.89) and medication group (1.10 ± 0.45;F =6.669,P ＜ 0.01).(4) There were pathologic alterations in the ultrastructure of neurons and synapses in the hippocampus of depression rats,which were improved by pharmacological intervention.(5) The number of p-CREB1 positive cells was related to the parameters of Morris water maze and synaptic morphology.Conclusion p-CREB1 expression is correlated with neuronal and synaptic plasticity,and venlafaxine may be effective through influencing the expression of p-CREB1 and neuronal and synaptic plasticity.%目的 探讨抑郁症模型大鼠海马区磷酸化环磷腺苷反应元件结合蛋白1(phospho cAMP response element-binding protein 1,p-CREB1)的表达变化对相应神经元、突触超微结构的影响及文拉法辛对p-CREB1表达及神经元、突触超微结构的作用.方法 采用随机数字表法将54只大鼠随机分为正常组(n=12)、抑郁症模型对照组(简称对照组,n=14)、抑郁症模型+生理盐水组(简称生理盐水组,n =14)和抑郁症模型+文拉法辛药物干预组(简称药物干预组,n=14).通过蔗糖水消耗实验、旷场实验检测动物的行为学表现,Morris水迷宫检测学习记忆能力.免疫组织化学检测海马区p-CREB1蛋白表达水平,RT-PCR检测CREB1 mRNA表达水平,透射电子显微镜观察海马区神经元、突触超微结构.p-CREB1阳性细胞数目与Morris水迷宫、突触形态学参数进行相关分析.结果 (1)行为学结果:对照组和生理盐水组蔗糖水消耗分别为(7.4±1.0)、(7.5±1.0) ml/100 g,低于正常组[(9.6±0.3) ml/100g]及药物干预组[(9.4±0.8)ml/100 g;F=17.851,P＜0.01)];Morris水迷宫定位航行实验逃避潜伏期分别为(61.1±10.5)、(59.0±10.6)s,大于正常组[(29.8±10.1)s]及药物干预组[(35.0±8.5)s;F =30.559,P＜0.01].(2)免疫组织化学结果:对照组和生理盐水组大鼠海马p-CREB1阳性细胞数分别为21.07±5.99和24.57±6.97,低于正常组(29.70 ±6.21)及药物干预组(41.50±11.95,F=16.497,P＜0.01).(3)RT-PCR结果:对照组和生理盐水组大鼠海马CREB1 mRNA吸光度比值分别为0.58±0.47和0.45±0.24,低于正常组(1.03±0.89)及药物干预组(1.10±0.45;F=6.669,P＜0.01).(4)电镜结果:抑郁症模型大鼠海马神经元和突触超微结构存在病理性改变,药物干预可使其改善.(5) p-CREB1阳性细胞数目与Morris水迷宫、突触形态学参数相关.结论 p-CREB1表达与神经元、突触可塑性有关,文拉法辛可能是通过影响p-CREB1表达和神经元、突触可塑性来发挥治疗作用.
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