Laboratory of Preclinical Neurobiology, Department of Neuroscience, Georgetown University Medical Center, Washington, DC 20057, USA.
Laboratory of Preclinical Neurobiology, Department of Neuroscience, Georgetown University Medical Center, Washington, DC 20057, USA.
Brain Behav Immun. 2020 Oct;89:371-379. doi: 10.1016/j.bbi.2020.07.023. Epub 2020 Jul 24.
Reduced synaptodendritic complexity appears to be a key feature in human immunodeficiency virus (HIV)-associated neurological disorder (HAND). Viral proteins, and in particular the envelope protein gp120, play a role in the pathology of synapses. Gp120 has been shown to increase both in vitro and in vivo the proneurotrophin brain-derived neurotrophic factor, which promotes synaptic simplification through the activation of the p75 neurotrophin receptor (p75NTR). To provide evidence that p75NTR plays a role in gp120-mediated loss of synapses in vivo, we intercrossed gp120tg mice with p75NTR null mice and used molecular, histological and behavioral analyses to establish a link between p75NTR and gp120-mediated synaptic simplification. Synaptosomes obtained from the striatum of gp120tg mice exhibited a significant increase in p75NTR levels concomitantly to a decrease in synaptic markers such as TrkB and PSD95. Analysis of striatal dendritic spines by Golgi staining revealed that gp120tg mice display a reduced proportion of mushroom-type spines in addition to fewer spines overall, when compared to wild type or gp120tg lacking one or two p75NTR alleles. Moreover, removal of one p75NTR allele in gp120 transgenic mice abolished the gp120-driven impairment on a task of striatal-dependent motor learning. These data indicate that p75NTR could be a key player in HIV-mediated synaptic simplification in the striatum.
突触复杂性降低似乎是人类免疫缺陷病毒（HIV）相关神经障碍（HAND）的一个关键特征。病毒蛋白，特别是包膜蛋白 gp120，在突触病理中起作用。已经表明，gp120 在体外和体内均可增加促神经原素脑源性神经营养因子，通过激活 p75 神经营养素受体（p75NTR）促进突触简化。为了提供 p75NTR 在 gp120 介导的体内突触丢失中起作用的证据，我们将 gp120tg 小鼠与 p75NTR 缺失小鼠进行杂交，并使用分子、组织学和行为分析来建立 p75NTR 与 gp120 介导的突触简化之间的联系。从 gp120tg 小鼠纹状体获得的突触体表现出 p75NTR 水平的显著增加，同时突触标记物如 TrkB 和 PSD95 减少。高尔基染色分析纹状体树突棘表明，与野生型或 gp120tg 缺乏一个或两个 p75NTR 等位基因相比，gp120tg 小鼠显示蘑菇型棘突的比例降低，并且棘突总数减少。此外，在 gp120 转基因小鼠中去除一个 p75NTR 等位基因消除了 gp120 驱动的纹状体依赖性运动学习任务的损伤。这些数据表明，p75NTR 可能是 HIV 介导的纹状体突触简化的关键参与者。
