肿瘤坏死因子-α对长时程增强（LTP）抑制作用的剖析揭示了一种p38丝裂原活化蛋白激酶依赖性机制，该机制与早期而非晚期LTP相关。

Dissection of tumor-necrosis factor-alpha inhibition of long-term potentiation (LTP) reveals a p38 mitogen-activated protein kinase-dependent mechanism which maps to early-but not late-phase LTP.

作者信息

Butler M P, O'Connor J J, Moynagh P N

机构信息

Department of Human Anatomy and Physiology, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Earlsfort Terrace, Dublin 2, Ireland.

出版信息

Neuroscience. 2004;124(2):319-26. doi: 10.1016/j.neuroscience.2003.11.040.

DOI:10.1016/j.neuroscience.2003.11.040

PMID:14980382

Abstract

The pro-inflammatory cytokine tumor-necrosis factor-alpha (TNF-alpha) is elevated in several neuropathological states that are associated with learning and memory deficits. Previous work has reported that TNF-alpha inhibits the induction of LTP in areas CA1 [Neurosci Lett 146 (1992) 176] and dentate gyrus [Neurosci Lett 203 (1996) 17]. The mechanism(s) underlying this process of inhibition have not to date been addressed. Here, we show that perfusion of TNF-alpha prior to long-term potentiation (LTP) inducing stimuli inhibited LTP, and that in late-LTP (3 h post-tetanus) a depression in synaptic field recordings was observed (68 +/- 5%, n = 6 versus control 175 +/- 7%, n = 6, P < 0.001). We investigated the involvement of the mitogen-activated protein kinase (MAPK) p38 in the inhibition of LTP by TNF-alpha as p38 MAPK has previously been shown to be involved in interleukin-1beta inhibition of LTP in the dentate gyrus [Neuroscience 93 (1999b) 57]. Perfusion of TNF-alpha led to an increase in the levels of phosphorylated p38 MAPK detectable in the granule cells of the dentate gyrus. The p38 MAPK inhibitor SB 203580 (1 microM) was found by itself to have no significant effect on either early or late phase LTP in the dentate gyrus. SB 203580 was found to significantly reverse the inhibition of early LTP by TNF-alpha (SB/TNF-alpha 174 +/- 5%, n = 6 versus TNF-alpha 120 +/- 7%, n = 6, P < 0.001, 1 h post-tetanus) to values comparable to control LTP (control 175 +/- 7%, n = 6). Interestingly however, the depressive effects of TNF-alpha on late LTP (2-3 h) were clearly not attenuated by p38 MAPK inhibition (SB/TNF-alpha 132 +/- 5%, n = 6 versus control LTP 175 +/- 7%, n = 6, P < 0.001, 3 h post-tetanus). This work suggests that TNF-alpha inhibition of LTP represents a biphasic response, a p38 MAPK-dependent phase that coincides with the early phase of LTP and a p38 MAPK independent phase that temporally maps to late LTP.

摘要

促炎细胞因子肿瘤坏死因子-α（TNF-α）在几种与学习和记忆缺陷相关的神经病理状态中升高。先前的研究报道，TNF-α抑制海马CA1区[《神经科学快报》146 (1992) 176]和齿状回[《神经科学快报》203 (1996) 17]中长时程增强（LTP）的诱导。迄今为止，这一抑制过程的潜在机制尚未得到探讨。在此，我们表明，在诱导LTP的刺激之前灌注TNF-α会抑制LTP，并且在晚期LTP（强直刺激后3小时）时，在突触场记录中观察到了抑制（68±5%，n = 6，与对照组175±7%，n = 6相比，P < 0.001）。我们研究了丝裂原活化蛋白激酶（MAPK）p38在TNF-α对LTP的抑制中的作用，因为先前已表明p38 MAPK参与白细胞介素-1β对齿状回中LTP的抑制[《神经科学》93 (1999b) 57]。灌注TNF-α导致在齿状回颗粒细胞中可检测到的磷酸化p38 MAPK水平升高。发现p38 MAPK抑制剂SB 203580（1 μM）本身对齿状回中LTP的早期或晚期阶段均无显著影响。发现SB 203580可显著逆转TNF-α对早期LTP的抑制作用（SB/TNF-α 174±5%，n = 6，与TNF-α 120±7%，n = 6相比，P < 0.001，强直刺激后1小时），使其值与对照LTP相当（对照175±7%，n = 6）。然而，有趣的是，p38 MAPK抑制并未明显减弱TNF-α对晚期LTP（2 - 3小时）的抑制作用（SB/TNF-α 132±5%，n = 6，与对照LTP 175±7%，n = 6相比，P < 0.001，强直刺激后3小时）。这项工作表明，TNF-α对LTP的抑制代表了一种双相反应，一个与LTP早期阶段一致的p38 MAPK依赖性阶段和一个在时间上与晚期LTP相对应的p38 MAPK非依赖性阶段。