HIV‐1 gp120 enhances giant depolarizing potentials via chemokine receptor CXCR4 in neonatal rat hippocampus
HIV‐1 gp120 enhances giant depolarizing potentials via chemokine receptor CXCR4 in neonatal rat hippocampus
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DOI：
10.1111/j.1460-9568.2006.04646.x
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发表时间：
2006-03
影响因子：
3.4
通讯作者：
A. Kasyanov;H. Tamamura;N. Fujii;H. Xiong
中科院分区：
文献类型：
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作者：
A. Kasyanov;H. Tamamura;N. Fujii;H. Xiong
在未成熟的海马区，巨去极化电位(GDPs)是由γ-氨基丁酸(GABA)产生的反复的网络驱动的突触事件，在新生生活中是去极化和兴奋性的。GDPs使未成熟神经元高度同步化，参与依赖活动的生长和突触形成。为了了解人类免疫缺陷病毒1型(HIV-1)在未成熟脑内感染对脑生长发育的影响，我们用全细胞斑贴技术研究了HIV-1包膜糖蛋白gp120对新生(P2-P6)SD大鼠海马片CA3锥体细胞自发产生GDPs的影响。在不影响被动膜特性的情况下，沐浴gp120以浓度依赖的方式产生持续的GDP频率增强，提示作用部位最有可能发生在神经网络上，而不是记录到的神经元上。趋化因子受体CXCR4的高度特异性拮抗剂T140可阻断gp120诱导的GDPs的增加，表明CXCR4参与了gp120诱导的GDPs的增加。基质细胞衍生因子-1α(SDF-1α)是唯一的CXCR4配体，其作用类似于gp120对GDPs的影响，支持CXCR4受体参与gp120诱导的GDPs的发生。进一步的研究表明，蛋白激酶A/C参与了gp120诱导的GDPs的增强。这些结果表明，gp120增强了新生大鼠海马区的GDPS。这种增强可能导致细胞内钙的过度增加和随之而来的神经元损伤，导致大脑和行为发育迟缓，就像在儿科艾滋病患者中看到的那样。
In the immature hippocampus, the giant depolarizing potentials (GDPs) are recurrent network‐driven synaptic events generated by γ–aminobutyric acid (GABA), which in neonatal life is depolarizing and excitatory. The GDPs enable a high degree of synchrony in immature neurons and participate in activity‐dependent growth and synapse formation. To understand how human immunodeficiency virus type one (HIV‐1) infection in the immature brain impairs brain growth and development, we studied the effects of HIV‐1 envelope glycoprotein, gp120, a viral toxin shed in abundance by infected cells, on spontaneous occurring GDPs recorded in the CA3 pyramidal cells in neonatal (P2–P6) Sprague–Dawley rat hippocampal slices using whole‐cell patch technique. Bath application of gp120 produced a sustained enhancement of GDP frequency in a concentration‐dependent manner without affecting passive membrane properties, suggesting that the site of action is most likely on neural network, other than on the recorded neurons. The gp120‐induced enhancement of GDPs was blocked by T140, a highly specific antagonist for the chemokine receptor, CXCR4, indicating the involvement of CXCR4 in the gp120‐induced increase of GDPs. Bath application of stromal cell‐derived factor‐1α (SDF‐1α), the only CXCR4 ligand, mimicked the effects of gp120 on GDPs, supporting the engagement of CXCR4 receptors in the gp120‐induced increase of GDP occurrence. Further studies revealed the involvement of protein kinase A/C in the gp120‐induced enhancement of GDPs. These results demonstrate that gp120 enhances GDPs in the neonatal rat hippocampus. This enhancement may cause an excessive increase in intracellular calcium and resultant neuronal injury, leading to retardation of the brain and behavioural development as seen in paediatric AIDS patients.