The physiological role of the lipid mediator on the synaptic plasticity in the central nervous system

将cPLA2作为已知在精神分裂症患者死后脑中异常表达的实质性脂质介质，探讨cPLA2在中枢神经系统中的生理作用及其与精神分裂症发病机制的关系。作为第一个实验，我们利用cPLA2基因缺陷小鼠研究了cPLA2的生理作用。基因敲除小鼠产生的幼崽数量与野生型小鼠一样多。他们没有表现出特别异常的外观和行为作为他们的表型。从四周大的老鼠的大脑中取出海马，然后准备切片样本。从CA1区获得电生理记录并进行分析。单次和多次刺激下，场态epsp和epsp的突触反应均无明显异常。LTP的振幅与野生型小鼠无显著性差异，但在敲除小鼠中，低频s的应用引起的长期抑制几乎完全被阻断。作为第二组实验，我们考察了作为cPLA2下游存在的花生四烯级联对LTD诱导的影响。通过膜片钳玻璃电极在突触后细胞中应用5-HETE不能恢复LTD诱导，而扩散到突触后细胞中的12-HPETE则恢复LTD诱导。我们得出结论，12-HPETE的活性是诱导小鼠海马神经元LTD的必要条件。我们研究了应激对大鼠脑功能的影响。对大鼠施加约束和强制游泳应力，进行电生理性能和行为测试。我们发现，应激1周后海马锥体神经元LTP的诱导几乎完全被抑制，而LTD的诱导不受影响。我们还发现空间学习被扭曲，声音惊吓反射被促进。有趣的是，这种促进作用在糖皮质激素受体（GR1）拮抗剂的存在下被抑制，这表明应激的作用至少部分是通过GR1的激活来实现的。我们还需要进一步研究GR1与脂质介质的活性关系。少

cPLA2 was used as the substantial lipid mediator which has been known abnormally expressed in the postmortem brain of the schizophrenic patients to investigate the physiological role of cPLA2 in the central nervous system in terms of the relation with the pathogenesis of schizophrenia. As the first experiment, we studied the physiological role of cPLA2 by using cPLA2 gene-deficient mouse. The knockout mice delivered as much number of pups as the wild-type mice. They revealed no particular abnormal appearance and behaviors as their phenotypes. The hippocampi were removed form the brain of four weeks old mice then slice samples were prepared. The electrophysiological recordings were obtained from the CA1 area then analyzed. The synaptic responses of filed EPSPs and EPSPs showed no particular abnormality by a single and multiple stimulation. The amplitude of LTP was not significantly different from wild-type mice, however, long-term depression induced by the application of low-frequency s … More tumuli was almost totally blocked in the knockout mice. As the second set of experiment, we examined the effect of arachidonic cascade which is existed as the downstream of cPLA2 on the induction of LTD. The application of 5-HETE in the postsynaptic cell through the patch clamp glass electrode did not recovered LTD induction, however, the application of 12-HPETE diffused into the postsynaptic cell recovered LTD induction. We concluded that the activity of 12-HPETE is required for the induction of LTD in the mouse hippocampal neurons. We investigated the effect of stress on the rat brain function. The restrain and force swimming stress were applied to the rat and electrophysiological properties and behavior tests were conducted. We found that LTP induction in the hippocampal pyramidal neurons was almost totally suppressed at one week after stress application, however, LTD induction was not affected. We also found that spatial learning was distorted and acoustic startle reflex was facilitated. Interestingly, this facilitation was inhibited in the presence of an antagonist of glucocorticoid receptor (GR1), suggesting that the effect of stress was at least partially through GR1 activation. We further need to investigate the relation of the activity between GR1 and lipid mediators. Less