Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, Florida.
J Neurophysiol. 2020 Apr 1;123(4):1332-1341. doi: 10.1152/jn.00029.2020. Epub 2020 Feb 26.
Human immunodeficiency virus (HIV)-1 transactivator of transcription protein (Tat) is a viral protein that promotes transcription of the HIV genome and possesses cell-signaling properties. Long-term exposure of central nervous system (CNS) tissue to HIV-1 Tat is theorized to contribute to HIV-associated neurodegenerative disorder (HAND). In the current study, we sought to directly evaluate the effect of HIV-1 Tat expression on the intrinsic electrophysiological properties of pyramidal neurons located in layer 2/3 of the medial prefrontal cortex and in area CA1 of the hippocampus. Toward that end, we drove Tat expression with doxycycline (100 mg·kg·day ip) in inducible Tat (iTat) transgenic mice for 7 days and then performed single-cell electrophysiological studies in acute tissue slices made through the prefrontal cortex and hippocampus. Control experiments were performed in doxycycline-treated G-tg mice, which retain the tetracycline-sensitive promoter but do not express Tat. Our results indicated that the predominant effects of HIV-1 Tat expression are excitatory in medial prefrontal cortical pyramidal neurons yet inhibitory in hippocampal pyramidal neurons. Notably, in these two populations, HIV-1 Tat expression produced differential effects on neuronal gain, membrane time constant, resting membrane potential, and rheobase. Similarly, we also observed distinct effects on action potential kinetics and afterhyperpolarization, as well as on the current-voltage relationship in subthreshold voltage ranges. Collectively, these data provide mechanistic evidence of complex and region-specific changes in neuronal physiology by which HIV-1 Tat protein may promote cognitive deficits associated with HAND. We drove expression of human immunodeficiency virus (HIV)-1 transactivator of transcription protein (Tat) protein in inducible Tat (iTat) transgenic mice for 7 days and then examined the effects on the intrinsic electrophysiological properties of pyramidal neurons located in the medial prefrontal cortex (mPFC) and in the hippocampus. Our results reveal a variety of specific changes that promote increased intrinsic excitability of layer II/III mPFC pyramidal neurons and decreased intrinsic excitability of hippocampal CA1 pyramidal neurons, highlighting both cell type and region-specific effects.
人类免疫缺陷病毒 (HIV)-1 转录激活蛋白 (Tat) 是一种病毒蛋白，可促进 HIV 基因组的转录，并具有细胞信号转导特性。理论上，中枢神经系统 (CNS) 组织长期暴露于 HIV-1 Tat 会导致与 HIV 相关的神经退行性疾病 (HAND)。在目前的研究中，我们试图直接评估 HIV-1 Tat 表达对位于内侧前额叶皮质 2/3 层和海马 CA1 区的锥体神经元固有电生理特性的影响。为此，我们使用强力霉素 (100mg·kg·day ip) 在诱导型 Tat (iTat) 转基因小鼠中诱导 Tat 表达 7 天，然后在通过前额叶皮质和海马制作的急性组织切片中进行单细胞电生理研究。在强力霉素处理的 G-tg 小鼠中进行了对照实验，这些小鼠保留了四环素敏感启动子，但不表达 Tat。我们的结果表明，HIV-1 Tat 表达的主要影响在内侧前额叶皮质锥体神经元中是兴奋性的，而在海马锥体神经元中是抑制性的。值得注意的是，在这两个群体中，HIV-1 Tat 表达对神经元增益、膜时间常数、静息膜电位和 rheobase 产生了不同的影响。同样，我们还观察到在动作电位动力学和后超极化以及亚阈值电压范围内的电流-电压关系方面也存在明显的影响。总的来说，这些数据提供了 HIV-1 Tat 蛋白促进 HAND 相关认知缺陷的神经元生理学复杂和区域特异性变化的机制证据。我们在诱导型 Tat (iTat) 转基因小鼠中诱导表达人类免疫缺陷病毒 (HIV)-1 转录激活蛋白 (Tat) 蛋白 7 天，然后检查其对位于内侧前额叶皮质 (mPFC) 和海马中的锥体神经元固有电生理特性的影响。我们的结果揭示了多种特定的变化，这些变化促进了 II/III 层 mPFC 锥体神经元固有兴奋性的增加和海马 CA1 锥体神经元固有兴奋性的降低，突出了细胞类型和区域特异性的影响。
