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

脂质介质对中枢神经系统突触可塑性的生理作用

基本信息

批准号：
17500213
负责人：
KATO Kunio
金额：
$ 2.18万
依托单位：
Kochi University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17500213/
关键词：
lipid mediator central nervous system arachidonic acid PLA2 synaptic plasticity long-term depression lipoxygenase knockout mouse 皮質伝達物質 cPLA2 arachidonic acid PAF hippocampus LTP LTD stress knockout mouse

项目摘要

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

以cPLA2作为已知在精神分裂症患者死后脑中异常表达的重要脂质介质，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。基因敲除小鼠产下的幼崽数量与野生型小鼠相同。他们没有表现出特殊的异常外观和行为。取4周龄小鼠脑内的海马区，制备切片标本。获得CA1区的电生理记录，并进行分析。单次和多次刺激后，野EPSPS和EPSPS的突触反应均无明显异常。LTP的波幅与野生型小鼠无显著差异，但应用低频S…引起的长期抑郁在基因敲除的小鼠中，更多的骚乱几乎完全被阻止。作为第二组实验，我们考察了存在于cPLA2下游的花生四烯酸级联对LTD诱导的影响。通过膜片钳玻璃电极将5-HETE应用于突触后细胞并未恢复LTD诱导，而应用12-HPETE弥散进入突触后细胞可恢复LTD诱导。我们的结论是，12-HPETE的活性是在小鼠海马神经元诱导LTD所必需的。我们研究了应激对大鼠脑功能的影响。对大鼠分别施加束缚应激和强迫游泳应激，并进行电生理特性和行为学测试。结果发现，应激后一周，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，听觉惊厥反射被促进。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，这表明应激的影响至少部分是通过GR1激活的。我们还需要进一步研究GR1的活性与脂质介质的关系。较少