HIV Tat excites D1 receptor-like expressing neurons from rat nucleus accumbens
HIV Tat excites D1 receptor-like expressing neurons from rat nucleus accumbens
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DOI：
10.1016/j.drugalcdep.2017.04.015
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发表时间：
2017-09-01
影响因子：
4.2
通讯作者：
Brailoiu, Eugen
中科院分区：
文献类型：
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作者：
Brailoiu, G. Cristina;Deliu, Elena;Brailoiu, Eugen
背景：HIV-1 感染和药物滥用经常同时发病，它们的关联大大增加了 HIV-1 诱发的神经病理学的严重程度。虽然伏隔核 (NAcc) 功能受到滥用药物的严重干扰，但我们对 HIV-1 感染如何影响 NAcc 知之甚少。方法：我们使用钙和电压成像来研究 HIV-1 转录反式激活因子 (Tat) 对大鼠 NAcc 的影响。基于之前的神经元研究，我们假设 Tat 调节 NAcc 神经元的细胞内 Ca2+ 稳态。结果：我们提供的证据表明，Tat 在表达 D1 样多巴胺受体的 NAcc 中型多棘神经元 (MSN) 中触发 Ca2+ 信号级联反应，导致神经元去极化。首先，Tat 诱导肌醇 1,4,5-三磷酸 (IP3) 受体介导的 Ca2+ 从内质网释放，然后 Ca2+ 和 Na+ 通过瞬时受体电位经典通道流入。阳离子的流入使膜去极化，促进额外的 Ca2+ 通过电压门控 P/Q 型 Ca2+ 通道进入，并打开河豚毒素不敏感的 Na+ 通道。通过激活这一机制，Tat 引发前馈去极化，增加 D1-磷脂酰肌醇连接的 NAcc MSN 的兴奋性。我们之前发现，仅当 IP3 生成机制同时启动时，可卡因才会直接靶向 NAcc 神经元（独立于多巴胺转运蛋白的抑制）。此处测试时，可卡因对 Tat 对胞质 Ca2+ 的作用产生剂量依赖性增强。结论：我们首次描述了 Nacc 的 MSN 中 HIV-1 Tat 触发的 Ca2+ 信号传导，涉及 TRPC 和去极化，以及可卡因对 Tat 作用的增强，这可能与可卡因滥用的 HIV-1 阳性患者的奖赏轴相关。
Background: HIV-1 infection and drug abuse are frequently co-morbid and their association greatly increases the severity of HIV-1-induced neuropathology. While nucleus accumbens (NAcc) function is severely perturbed by drugs of abuse, little is known about how HIV-1 infection affects NAcc.Methods: We used calcium and voltage imaging to investigate the effect of HIV-1 trans-activator of transcription (Tat) on rat NAcc. Based on previous neuronal studies, we hypothesized that Tat modulates intracellular Ca2+ homeostasis of NAcc neurons.Results: We provide evidence that Tat triggers a Ca2+ signaling cascade in NAcc medium spiny neurons (MSN) expressing D1-like dopamine receptors leading to neuronal depolarization. Firstly, Tat induced inositol 1,4,5-trisphsophate (IP3) receptor-mediated Ca2+ release from endoplasmic reticulum, followed by Ca2+ and Na+ influx via transient receptor potential canonical channels. The influx of cations depolarizes the membrane promoting additional Ca2+ entry through voltage-gated P/Q-type Ca2+ channels and opening of tetrodotox-insensitive Na+ channels. By activating this mechanism, Tat elicits a feed-forward depolarization increasing the excitability of D1-phosphatidylinositol-linked NAcc MSN. We previously found that cocaine targets NAcc neurons directly (independent of the inhibition of dopamine transporter) only when IP3-generating mechanisms are concomitantly initiated. When tested here, cocaine produced a dose-dependent potentiation of the effect of Tat on cytosolic Ca2+.Conclusion: We describe for the first time a HIV-1 Tat-triggered Ca2+ signaling in MSN of NAcc involving TRPC and depolarization and a potentiation of the effect of Tat by cocaine, which may be relevant for the reward axis in cocaine-abusing HIV-1-positive patients.