Lipid signaling in cytosolic phospholipase A2α-cyclooxygenase-2 cascade mediates cerebellar long-term depression and motor learning
Lipid signaling in cytosolic phospholipase A2α-cyclooxygenase-2 cascade mediates cerebellar long-term depression and motor learning
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DOI：
10.1073/pnas.0915020107
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发表时间：
2010-02-16
影响因子：
11.1
通讯作者：
Ito, Masao
中科院分区：
文献类型：
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作者：
Le, Tung Dinh;Shirai, Yoshinori;Ito, Masao
在这项研究中，我们显示了脂质信号在长期抑郁症（LTD）中的重要作用，即小脑浦肯野细胞的突触可塑性。在小鼠脑切片中，我们发现cPLA（2）alpha敲除阻断LTD诱导，补充花生四烯酸（AA）或前列腺素（PG）D-2或E-2可挽救LTD诱导。此外，环氧合酶（考克斯）-2抑制剂阻断LTD，通过补充PGD（2）/E-2来挽救。当在LTD诱导刺激开始后5-15分钟的时间窗内应用这些试剂时，就会发生阻断或拯救。此外，PGD（2）/E-2促进PKC激活剂对LTD的化学诱导，但不能挽救PKC抑制剂阻断的LTD。我们的结论是PGD（2）/E-2与PKC共同介导LTD，并提出了它们相互作用的可能途径。最后，我们在清醒的小鼠中证实了cPLA（2）α缺乏或考克斯-2抑制会减弱视动性眼球运动的短期适应，支持LTD是运动学习的基础的观点。
In this study, we show the crucial roles of lipid signaling in long-term depression (LTD), that is, synaptic plasticity prevailing in cerebellar Purkinje cells. In mouse brain slices, we found that cPLA(2)alpha knockout blocked LTD induction, which was rescued by replenishing arachidonic acid (AA) or prostaglandin (PG) D-2 or E-2. Moreover, cyclooxygenase (COX)-2 inhibitors block LTD, which is rescued by supplementing PGD(2)/E-2. The blockade or rescue occurs when these reagents are applied within a time window of 5-15 min following the onset of LTD-inducing stimulation. Furthermore, PGD(2)/E-2 facilitates the chemical induction of LTD by a PKC activator but is unable to rescue the LTD blocked by a PKC inhibitor. We conclude that PGD(2)/E-2 mediates LTD jointly with PKC, and suggest possible pathways for their interaction. Finally, we demonstrate in awake mice that cPLA(2)alpha deficiency or COX-2 inhibition attenuates short-term adaptation of optokinetic eye movements, supporting the view that LTD underlies motor learning.