The Neurophysiology Laboratory, Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198-5880, USA.
The Neurophysiology Laboratory, Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198-5880, USA.
Neurobiol Dis. 2022 Jun 15;168:105712. doi: 10.1016/j.nbd.2022.105712. Epub 2022 Mar 22.
Methamphetamine (Meth) abuse and human immunodeficiency virus type 1 (HIV-1) infection are two major public health problems worldwide. Being frequently comorbid with HIV-1 infection, Meth abuse exacerbates neurocognitive impairment in HIV-1-infected individuals even in the era of combined antiretroviral therapy. While a large body of research have studied the individual effects of Meth and HIV-1 envelope glycoprotein 120 (gp120) in the brain, far less has focused on their synergistic influence. Moreover, it is well-documented that the hippocampus is the primary site of spatial learning and long-term memory formation. Dysregulation of activity-dependent synaptic transmission and plasticity in the hippocampus is believed to impair neurocognitive function. To uncover the underlying mechanisms for increased incidence and severity of HIV-1-associated neurocognitive disorders (HAND) in HIV-1-infected patients with Meth abuse, we investigated acute individual and combined effects of Meth (20 μM) and gp120 (200 pM) on synaptic transmission and plasticity in the CA1 region of young adult male rat hippocampus, a brain region known to be vulnerable to HIV-1 infection. Our results showed that acute localized application of Meth and gp120 each alone onto the CA1 region reduced short-term dynamics of input-output responses and frequency facilitation, and attenuated long-term potentiation (LTP) induced by either high frequency stimulation or theta burst stimulation. A synergistic augmentation on activity-dependent synaptic plasticity was observed when Meth and gp120 were applied in combination. Paired-pulse facilitation results exhibited an altered facilitation ratio, suggesting a presynaptic site of action. Further studies revealed an involvement of microglia NLRP3 inflammasome activation in Meth augmentation of gp120-mediated attenuation of LTP. Taken together, our results demonstrated Meth augmented gp120 attenuation of LTP in the hippocampus. Since LTP is the accepted experimental analog of learning at the synaptic level, such augmentation may underlie Meth exacerbation of HAND observed clinically.
甲基苯丙胺（冰毒）滥用和人类免疫缺陷病毒 1 型（HIV-1）感染是全球两个主要的公共卫生问题。在感染 HIV-1 的人群中，冰毒滥用经常与 HIV-1 感染并存，即使在联合抗逆转录病毒治疗时代，也会加剧神经认知障碍。虽然大量研究已经研究了冰毒和 HIV-1 包膜糖蛋白 120（gp120）在大脑中的单独作用，但很少关注它们的协同影响。此外，众所周知，海马体是空间学习和长期记忆形成的主要部位。海马体中活性依赖性突触传递和可塑性的失调被认为会损害神经认知功能。为了揭示冰毒滥用的 HIV-1 感染患者中 HIV-1 相关神经认知障碍（HAND）发生率和严重程度增加的潜在机制，我们研究了急性个体和 Meth（20μM）和 gp120（200 pM）联合对年轻成年雄性大鼠海马体 CA1 区突触传递和可塑性的影响，已知该脑区易受 HIV-1 感染。我们的研究结果表明，单独将 Meth 和 gp120 急性局部应用于 CA1 区会降低输入-输出反应的短期动力学和频率易化，并减弱高频刺激或 theta 爆发刺激诱导的长时程增强（LTP）。当 Meth 和 gp120 联合应用时，观察到对活性依赖性突触可塑性的协同增强。成对脉冲易化结果显示易化比发生改变，表明存在突触前作用部位。进一步的研究表明，Meth 增强了 gp120 介导的 LTP 减弱作用，涉及小胶质细胞 NLRP3 炎性小体的激活。总之，我们的研究结果表明，Meth 增强了 gp120 对 LTP 的减弱作用。由于 LTP 是突触水平学习的公认实验模拟，因此这种增强可能是临床上观察到冰毒加剧 HAND 的基础。
