Krogh Kelly A, Green Matthew V, Thayer Stanley A
Department of Pharmacology, University of Minnesota, 6-120 Jackson Hall, 321 Church Street SE, Minneapolis, MN 55455, USA.
Curr HIV Res. 2014;12(6):406-14. doi: 10.2174/1570162x13666150121110402.
HIV-associated neurocognitive disorders (HAND) afflict approximately half of HIV-infected patients. The HIV-1 transactivator of transcription (Tat) protein is released by infected cells and contributes to the pathogenesis of HAND, but many of the underlying mechanisms remain poorly understood. Here we used fura-2-based Ca(2+) imaging and whole-cell patch-clamp recording to study the effects of Tat on the spontaneous synaptic activity that occurs in networked rat hippocampal neurons in culture. Tat triggered aberrant network activity that exhibited a decrease in the frequency of spontaneous action potential bursts and Ca(2+) spikes with a simultaneous increase in burst duration and Ca(2+) spike amplitude. These network changes were apparent after 4 h treatment with Tat and required the low-density lipoprotein receptor-related protein (LRP). Interestingly, Tat-induced changes in network activity adapted during 24 h exposure. The activity returned to control levels in the maintained presence of Tat for 24 h. These observations indicate that Tat causes aberrant network activity, which is dependent on LRP, and adapts following prolonged exposure. Changes in network excitability may contribute to Tat-induced neurotoxicity in vitro and seizure disorders in vivo. Adaptation of neural networks may be a neuroprotective response to the sustained presence of the neurotoxic protein Tat and could underlie the behavioral and electrophysiological changes observed in HAND.
与人类免疫缺陷病毒（HIV）相关的神经认知障碍（HAND）影响着约一半的HIV感染患者。HIV-1转录激活因子（Tat）蛋白由受感染细胞释放，并在HAND的发病机制中起作用，但许多潜在机制仍知之甚少。在这里，我们使用基于fura-2的Ca²⁺成像和全细胞膜片钳记录来研究Tat对培养的联网大鼠海马神经元中自发突触活动的影响。Tat引发异常的网络活动，表现为自发动作电位爆发和Ca²⁺尖峰频率降低，同时爆发持续时间和Ca²⁺尖峰幅度增加。在用Tat处理4小时后，这些网络变化很明显，并且需要低密度脂蛋白受体相关蛋白（LRP）。有趣的是，Tat诱导的网络活动变化在24小时暴露期间会适应。在持续存在Tat 24小时的情况下，活动恢复到对照水平。这些观察结果表明，Tat会导致异常的网络活动，这依赖于LRP，并且在长时间暴露后会适应。网络兴奋性的变化可能导致Tat在体外诱导神经毒性以及在体内引发癫痫障碍。神经网络的适应可能是对神经毒性蛋白Tat持续存在的一种神经保护反应，并且可能是HAND中观察到的行为和电生理变化的基础。
