Kasyanov Alexander, Tamamura Hirokazu, Fujii Nobutaka, Xiong Huangui
Neurophysiology Laboratory, Center for Neurovirology and Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, USA.
Eur J Neurosci. 2006 Mar;23(5):1120-8. doi: 10.1111/j.1460-9568.2006.04646.x.
In the immature hippocampus, the giant depolarizing potentials (GDPs) are recurrent network-driven synaptic events generated by gamma-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-1alpha (SDF-1alpha), 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.
在未成熟的海马体中，巨大去极化电位（GDPs）是由γ-氨基丁酸（GABA）产生的反复出现的网络驱动突触事件，在新生儿期，GABA具有去极化和兴奋性作用。GDPs使未成熟神经元具有高度同步性，并参与依赖活动的生长和突触形成。为了了解未成熟大脑中的人类免疫缺陷病毒1型（HIV-1）感染如何损害大脑生长和发育，我们使用全细胞膜片钳技术研究了HIV-1包膜糖蛋白gp120（一种被感染细胞大量释放的病毒毒素）对新生（P2-P6）Sprague-Dawley大鼠海马体切片CA3锥体细胞中自发出现的GDPs的影响。浴槽中加入gp120以浓度依赖的方式持续增强GDP频率，而不影响被动膜特性，这表明作用位点最可能在神经网络上，而非记录的神经元上。gp120诱导的GDPs增强被T140（趋化因子受体CXCR4的高度特异性拮抗剂）阻断，表明CXCR4参与了gp120诱导的GDPs增加。浴槽中加入基质细胞衍生因子-1α（SDF-1α，CXCR4的唯一配体）模拟了gp120对GDPs的作用，支持CXCR4受体参与gp120诱导的GDPs出现增加。进一步研究揭示蛋白激酶A/C参与了gp120诱导的GDPs增强。这些结果表明，gp120增强了新生大鼠海马体中的GDPs。这种增强可能导致细胞内钙过度增加并造成神经元损伤，导致如儿科艾滋病患者所见的大脑和行为发育迟缓。
