Graduate Program in Neuroscience, University of Minnesota Medical School, Minneapolis, MN, 55455, USA.
Graduate Program in Neuroscience, University of Minnesota Medical School, Minneapolis, MN, 55455, USA; Department of Pharmacology, University of Minnesota Medical School, Minneapolis, MN, 55455, USA.
Neuropharmacology. 2019 May 1;149:161-168. doi: 10.1016/j.neuropharm.2019.02.024. Epub 2019 Feb 20.
HIV-Associated Neurocognitive disorder (HAND) affects nearly half of infected patients. The HIV envelope protein gp120 is shed by infected cells and is a potent neurotoxin in vitro that reproduces many aspects of HAND when expressed in vivo. Here, we show that HIV gp120 increases the amplitude of a tonic current mediated by γ-aminobutyric acid type-A receptors (GABARs). Treating rat hippocampal cultures with 600 pM gp120 for 4 h increased a tonic bicuculline-sensitive current, which remained elevated for 24 h. The increased current resulted from upregulation of extrasynaptic α5-containing GABARs, as indicated by inhibition with the selective inverse agonist basmisanil. Treatment with gp120 increased α5-GABAR immunoreactivity on the cell surface without new protein synthesis. The increase in tonic inhibition was prevented by a C-X-C chemokine receptor type 4 (CXCR4) antagonist or elimination of microglia from the culture. Treatment with interleukin-1β (IL-1β) increased the tonic current and an IL-1 receptor antagonist blocked the gp120-evoked response. Pharmacological or genetic inhibition of p38 mitogen-activated protein kinase (MAPK) prevented the gp120-evoked increase in tonic current and direct activation of a mutant form of p38 MAPK expressed in neurons increased the current. Collectively, these data show that gp120 activates CXCR4 to stimulate microglia to release IL-1β. Subsequent stimulation of IL-1 receptors activates p38 MAPK in neurons leading to the upregulation of α5-containing GABARs. Increased tonic inhibition impairs neuroplasticity and inhibition of α5-containing GABARs improves cognitive function in disease models. Thus, gp120-induced upregulation of α5-containing GABARs presents a novel therapeutic target for HAND.
HIV 相关神经认知障碍（HAND）影响近半数感染患者。HIV 包膜蛋白 gp120 由受感染细胞释放，是一种有效的体外神经毒素，当在体内表达时可复制 HAND 的许多方面。在这里，我们表明 HIV gp120 增加了 γ-氨基丁酸 A 型受体 (GABARs) 介导的紧张性电流的幅度。用 600 pM gp120 处理大鼠海马培养物 4 小时会增加紧张性的毒蕈碱敏感电流，该电流持续升高 24 小时。增加的电流是由于突触外含有 α5 的 GABARs 的上调所致，这表明选择性反向激动剂 basmisanil 可抑制电流。gp120 处理增加了细胞表面上 α5-GABAR 的免疫反应性，而无需新的蛋白质合成。CXCR4 拮抗剂或从小鼠海马培养物中消除小胶质细胞可防止紧张性抑制增加。白细胞介素-1β (IL-1β) 的处理增加了紧张性电流，而 IL-1 受体拮抗剂阻断了 gp120 诱导的反应。p38 丝裂原活化蛋白激酶 (MAPK) 的药理学或遗传学抑制可防止 gp120 诱导的紧张性电流增加，并直接激活神经元中表达的突变形式的 p38 MAPK 增加了电流。总的来说，这些数据表明 gp120 通过激活 CXCR4 来刺激小胶质细胞释放白细胞介素-1β。随后，白细胞介素-1 受体的刺激激活神经元中的 p38 MAPK，导致含有 α5 的 GABARs 的上调。增加的紧张性抑制会损害神经可塑性，并且抑制含有 α5 的 GABARs 可改善疾病模型中的认知功能。因此，gp120 诱导的含有 α5 的 GABARs 的上调为 HAND 提供了一个新的治疗靶点。
