Graduate Program in Neuroscience, University of Minnesota Medical School, Minneapolis, MN 55455.
Graduate Program in Neuroscience, University of Minnesota Medical School, Minneapolis, MN 55455
eNeuro. 2020 Jun 19;7(3). doi: 10.1523/ENEURO.0119-20.2020. Print 2020 May/Jun.
Despite the success of antiretroviral therapy in suppressing viral load, nearly half of the 37 million people infected with HIV experience cognitive and motor impairments, collectively classified as HIV-associated neurocognitive disorders (HAND). In the CNS, HIV-infected microglia release neurotoxic agents that act indirectly to elicit excitotoxic synaptic injury. HIV trans-activator of transcription (Tat) protein is one such neurotoxin that is thought to play a major role in the neuropathogenesis of HAND. The endocannabinoid (eCB) system provides on-demand neuroprotection against excitotoxicity, and exogenous cannabinoids attenuate neurotoxicity in animal models of HAND. Whether this neuroprotective system is altered in the presence of HIV is unknown. Here, we examined the effects of Tat on the eCB system in rat primary hippocampal cultures. Using whole-cell patch-clamp electrophysiology, we measured changes in retrograde eCB signaling following exposure to Tat. Treatment with Tat significantly reduced the magnitude of depolarization-induced suppression of excitation (DSE) in a graded manner over the course of 48 h. Interestingly, Tat did not alter this form of short-term synaptic plasticity at inhibitory terminals. The Tat-induced decrease in eCB signaling resulted from impaired CB receptor (CBR)-mediated presynaptic inhibition of glutamate release. This novel loss-of-function was particularly dramatic for low-efficacy agonists such as the eCB 2-arachidonoylglycerol (2-AG) and Δ-tetrahydrocannabinol (Δ-THC), the main psychoactive ingredient in marijuana. Our observation that HIV Tat decreases CBR function suggests that eCB-mediated neuroprotection may be reduced ; this effect of Tat may contribute to synaptodendritic injury in HAND.
尽管抗逆转录病毒疗法在抑制病毒载量方面取得了成功，但仍有近 3700 万感染 HIV 的人出现认知和运动障碍，这些障碍统称为 HIV 相关神经认知障碍（HAND）。在中枢神经系统中，感染 HIV 的小胶质细胞释放出神经毒性物质，间接引起兴奋性突触损伤。HIV 转录激活物（Tat）蛋白就是这样一种神经毒素，它被认为在 HAND 的神经发病机制中起主要作用。内源性大麻素（eCB）系统提供了针对兴奋性毒性的按需神经保护，外源性大麻素可减轻 HAND 动物模型中的神经毒性。目前尚不清楚在 HIV 存在的情况下，这种神经保护系统是否会发生改变。在这里，我们研究了 Tat 对大鼠原代海马培养物中 eCB 系统的影响。使用全细胞膜片钳电生理学，我们测量了 Tat 暴露后逆行 eCB 信号的变化。Tat 的处理以逐渐的方式在 48 小时内显著降低了去极化诱导的兴奋抑制（DSE）的幅度。有趣的是，Tat 并没有改变这种在抑制性末端的短期突触可塑性形式。eCB 信号的 Tat 诱导减少是由于 CB 受体（CBR）介导的谷氨酸释放的突触前抑制受损所致。这种新型的功能丧失对于低效能激动剂（如内源性大麻素 2-花生四烯酸甘油（2-AG）和 Δ-四氢大麻酚（Δ-THC））特别明显，后者是大麻中的主要精神活性成分。我们观察到 HIV Tat 降低了 CBR 功能，这表明 eCB 介导的神经保护可能减少；Tat 的这种作用可能导致 HAND 中的突触树突损伤。
