Phospholipase D1-promoted release of tissue plasminogen activator facilitates neurite outgrowth
Phospholipase D1-promoted release of tissue plasminogen activator facilitates neurite outgrowth
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DOI：
10.1523/jneurosci.4850-04.2005
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发表时间：
2005-02-16
影响因子：
5.3
通讯作者：
Tsirka, SE
中科院分区：
文献类型：
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作者：
Zhang, Y;Kanaho, Y;Tsirka, SE
颞叶癫痫 (TLE) 是最常见的癫痫形式，影响约 1-2% 的人口。 TLE 引起的癫痫发作事件的特点是异常的海马苔藓纤维萌芽和影响大脑功能的塑性反应。癫痫易感性由组织纤溶酶原激活剂 (tPA) 调节，其正常生理作用包括通过启动蛋白水解级联来促进苔藓纤维通路中的突触重组，从而裂解细胞外基质成分并影响神经突延伸。在兴奋事件期间，tPA 集中在生长锥处并选择性地从生长锥分泌。然而，癫痫发作诱导的突触发生过程中 tPA 释放的机制尚不清楚。我们在这里研究信号酶磷脂酶 D1 (PLD1) 的潜在作用，它促进非 CNS 细胞类型中受调节的胞吐作用，并且我们之前已经证明在癫痫发作诱导的苔藓纤维发芽期间海马神经元的表达增加。我们现在表明，在培养的神经元中野生型 PLD1 的过度表达会促进 tPA 释放和 tPA 依赖性神经突延伸，而失活 PLD1 等位基因的过度表达或 PLD1 的药理学抑制会抑制 tPA 释放。同样，在癫痫诱导模型中，将野生型PLD1病毒递送至海马体可促进tPA分泌和苔藓纤维发芽，而失活的PLD1等位基因则抑制tPA释放并引起与tPA(-/-)小鼠观察到的类似的钝化和异常苔藓纤维延伸。总之，这些发现表明，PLD1 内源性地发挥调节 tPA(-/-) 分泌的作用，从而在神经元刺激升高的情况下调节苔藓纤维的延伸，例如 TLE 中所见的情况。
Temporal lobe epilepsy (TLE) is the most common form of epilepsy, affecting similar to1-2% of the population. Seizure events resulting from TLE are characterized by aberrant hippocampal mossy fiber sprouting and plastic responses that affect brain function. Seizure susceptibility is modulated by the enzyme tissue plasminogen activator (tPA), the normal physiological role of which includes promotion of synaptic reorganization in the mossy fiber pathway by initiating a proteolytic cascade that cleaves extracellular matrix components and influences neurite extension. tPA is concentrated at and selectively secreted from growth cones during excitatory events. However, the mechanisms underlying tPA release during seizure-induced synaptogenesis are not well understood. We examine here potential roles for the signaling enzyme phospholipase D1 (PLD1), which promotes regulated exocytosis in non-CNS cell types, and which we previously demonstrated increases in expression in hippocampal neurons during seizure-induced mossy fiber sprouting. We now show that overexpression of wild-type PLD1 in cultured neurons promotes tPA release and tPA-dependent neurite extension, whereas overexpression of an inactive PLD1 allele or pharmacological inhibition of PLD1 inhibits tPA release. Similarly, viral delivery of wild-type PLD1 into the hippocampus facilitates tPA secretion and mossy fiber sprouting in a seizure-inducing model, whereas the inactive PLD1 allele inhibits tPA release and elicits blunted and abnormal mossy fiber extension similar to that observed for tPA(-/-) mice. Together, these findings suggest that PLD1 functions endogenously to regulate tPA(-/-) secretion and thus mossy fiber extension in the setting of elevated neuronal stimulation, such as that seen in TLE.