Department of Psychology & Neuroscience, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Department of Chemistry & Biochemistry, North Carolina Central University, Durham, NC 27707, USA.
Cells. 2022 Mar 2;11(5):857. doi: 10.3390/cells11050857.
(1) Background. The endocannabinoid (eCB) system, which regulates physiological and cognitive processes, presents a promising therapeutic target for treating HIV-associated neurocognitive disorders (HAND). Here we examine whether upregulating eCB tone has potential protective effects against HIV-1 Tat (a key HIV transactivator of transcription) protein-induced alterations in synaptic activity. (2) Methods. Whole-cell patch-clamp recordings were performed to assess inhibitory GABAergic neurotransmission in prefrontal cortex slices of Tat transgenic male and female mice, in the presence and absence of the fatty acid amide hydrolase (FAAH) enzyme inhibitor PF3845. Western blot and mass spectrometry analyses assessed alterations of cannabinoid receptor and enzyme protein expression as well as endogenous ligands, respectively, to determine the impact of Tat exposure on the eCB system. (3) Results. GABAergic activity was significantly altered upon Tat exposure based on sex, whereas the effectiveness of PF3845 to suppress GABAergic activity in Tat transgenic mice was not altered by Tat or sex and involved CBR-related mechanisms that depended on calcium signaling. Additionally, our data indicated sex-dependent changes for AEA and related non-eCB lipids based on Tat induction. (4) Conclusion. Results highlight sex- and/or Tat-dependent alterations of GABAergic activity and eCB signaling in the prefrontal cortex of Tat transgenic mice and further increase our understanding about the role of FAAH inhibition in neuroHIV.
(1) 背景：内源性大麻素（eCB）系统调节生理和认知过程，是治疗 HIV 相关神经认知障碍（HAND）的有前途的治疗靶点。在这里，我们研究了上调 eCB 张力是否对 HIV-1 Tat（一种关键的 HIV 转录激活蛋白）蛋白诱导的突触活动改变具有潜在的保护作用。
(2) 方法：在存在和不存在脂肪酸酰胺水解酶（FAAH）抑制剂 PF3845 的情况下，进行全细胞膜片钳记录，以评估前额叶皮层切片中 Tat 转基因雄性和雌性小鼠的抑制性 GABA 能神经传递。Western blot 和质谱分析分别评估大麻素受体和酶蛋白表达以及内源性配体的改变，以确定 Tat 暴露对 eCB 系统的影响。
(3) 结果：基于性别，Tat 暴露后 GABA 能活性发生显著改变，而 PF3845 抑制 Tat 转基因小鼠 GABA 能活性的效果不受 Tat 或性别影响，并且涉及依赖钙信号的 CBR 相关机制。此外，我们的数据表明，基于 Tat 诱导，AEA 和相关非 eCB 脂质存在性别依赖性变化。
(4) 结论：结果强调了 Tat 转基因小鼠前额叶皮层中 GABA 能活性和 eCB 信号的性别依赖性和/或 Tat 依赖性改变，并进一步增加了我们对 FAAH 抑制在神经 HIV 中的作用的理解。
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