Chronic LPS exposure produces changes in intrinsic membrane properties and a sustained IL-β-dependent increase in GABAergic inhibition in hippocampal CA1 pyramidal neurons
Chronic LPS exposure produces changes in intrinsic membrane properties and a sustained IL-β-dependent increase in GABAergic inhibition in hippocampal CA1 pyramidal neurons
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DOI：
10.1002/hipo.20086
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发表时间：
2005-01-01
期刊：
影响因子：
3.5
通讯作者：
Williams, S
中科院分区：
文献类型：
--
作者：
Hellstrom, IC;Danik, M;Williams, S
据报道，慢性炎症是包括阿尔茨海默病和唐氏综合征在内的许多慢性神经系统疾病的诱导和进展的重要因素。据信炎症可促进突触功能障碍，这是一种部分由促炎细胞因子如白介素-1 β（IL-1 β）介导的作用。然而，IL-1 β和其他细胞因子在突触传递中的作用仍然知之甚少。在这项研究中，我们研究了如何在海马锥体神经元突触传递和神经元兴奋性的慢性炎症引起的暴露器官切片细菌细胞壁产物脂多糖（LPS）的影响。我们报告说，CA 1锥体神经元记录在整个细胞从切片先前暴露于LIPS 7天的静息膜电位和动作电位的性质类似的控制。然而，它们具有显著较低的膜电阻和更高的动作电位阈值，并显示出较慢的动作电位放电频率。此外，慢性LPS暴露后，突触后γ-氨基丁酸（GABA）能电位的振幅，但兴奋性GABA能突触后电位的振幅，显着较大。有趣的是，IL-1受体拮抗剂（IL-1 Ra）与LPS同时共孵育可阻止GABA能传递的增加，但不能降低内在神经元兴奋性。最后，我们证实LPS显著增加了IL-1 β和ILAP依赖性IL-6在培养基中的水平，持续2天，然后恢复到基线水平。我们的结论是，CA 1锥体神经元切片长期暴露于LPS表现出持续的兴奋性下降，由于内在膜兴奋性和增强突触GABA能输入的组合减少，后者依赖于IL-1 β。因此，海马慢性炎症在神经元和突触功能中产生ILAP依赖性和非依赖性效应，这可能显著导致认知障碍。(c)2005 Wiley-Liss，Inc.
Chronic inflammation has been reported to be a significant factor in the induction and progression of a number of chronic neurological disorders including Alzheimer's disease and Down syndrome. it is believed that inflammation may promote synaptic dysfunction, an effect that is mediated in part by pro-inflammatory cytokines such as interleukin-1 beta (IL-1 beta). However, the role of IL-1 beta and other cytokines in synaptic transmission is still poorly understood. In this study, we have investigated how synaptic transmission and neuronal excitability in hippocampal pyramidal neurons are affected by chronic inflammation induced by exposing organotypic slices to the bacterial cell-wall product lipopolysaccharide (LPS). We report that CA1 pyramidal neurons recorded in whole cell from slices previously exposed to LIPS for 7 days had resting membrane potential and action potential properties similar to those of the controls. However, they had significantly lower membrane resistance and a more elevated action potential threshold, and displayed a slower frequency of action potential discharge. Moreover, the amplitude of pharmacologically isolated postsynaptic gamma-aminobutyric acid (GABA)ergic potentials, but not excitatory glutamatergic postsynaptic potentials, was significantly larger following chronic LPS exposure. Interestingly, co-incubation of the IL-1 receptor antagonist (IL-1Ra) concurrently with LPS prevented the increase in GABAergic transmission, but not the reduction in intrinsic neuronal excitability. Finally, we confirmed that LPS dramatically increased IL-1 beta, and ILAP-dependent IL-6 levels in the culture medium for 2 days before returning to baseline. We conclude that CA1 pyramidal neurons in slices chronically exposed to LPS show a persistent decrease in excitability due to a combined decrease in intrinsic membrane excitability and an enhancement in synaptic GABAergic input, the latter being dependent on IL-1 beta. Therefore, chronic inflammation in hippocampus produces ILAP-dependent and -independent effects in neuronal and synaptic function that could contribute significantly to cognitive disturbances. (c) 2005 Wiley-Liss, Inc.