Kaufer D, Friedman A, Seidman S, Soreq H
Department of Biological Chemistry, The Alexander Silberman Life Sciences Institute, The Hebrew University of Jerusalem, Israel.
Nature. 1998 May 28;393(6683):373-7. doi: 10.1038/30741.
Acute traumatic stress may lead to post-traumatic stress disorder (PTSD), which is characterized by delayed neuropsychiatric symptoms including depression, irritability, and impaired cognitive performance. Curiously, inhibitors of the acetylcholine-hydrolysing enzyme acetylcholinesterase may induce psychopathologies that are reminiscent of PTSD. It is unknown how a single stressful event mediates long-term neuronal plasticity. Moreover, no mechanism has been proposed to explain the convergent neuropsychological outcomes of stress and of acetylcholinesterase inhibition. However, acute stress elicits a transient increase in the amounts released of the neurotransmitter acetylcholine and a phase of enhanced neuronal excitability. Inhibitors of acetylcholinesterase also promote enhanced electrical brain activity, presumably by increasing the survival of acetylcholine at the synapse. Here we report that there is similar bidirectional modulation of genes that regulate acetylcholine availability after stress and blockade of acetylcholinesterase. These calcium-dependent changes in gene expression coincide with phases of rapid enhancement and delayed depression of neuronal excitability. Both of these phases are mediated by muscarinic acetylcholine receptors. Our results suggest a model in which robust cholinergic stimulation triggers rapid induction of the gene encoding the transcription factor c-Fos. This protein then mediates selective regulatory effects on the long-lasting activities of genes involved in acetylcholine metabolism.
急性创伤性应激可能导致创伤后应激障碍（PTSD），其特征为出现延迟性神经精神症状，包括抑郁、易怒和认知功能受损。奇怪的是，乙酰胆碱水解酶乙酰胆碱酯酶的抑制剂可能诱发类似于创伤后应激障碍的精神病理学症状。尚不清楚单一应激事件如何介导长期的神经元可塑性。此外，尚未提出任何机制来解释应激和乙酰胆碱酯酶抑制所导致的趋同神经心理学结果。然而，急性应激会引发神经递质乙酰胆碱释放量的短暂增加以及神经元兴奋性增强的阶段。乙酰胆碱酯酶抑制剂也会促进脑电活动增强，推测这是通过增加突触处乙酰胆碱的存留来实现的。在此我们报告，应激和乙酰胆碱酯酶阻断后，在调节乙酰胆碱可用性的基因方面存在类似的双向调节。这些依赖钙的基因表达变化与神经元兴奋性快速增强和延迟性抑制的阶段相吻合。这两个阶段均由毒蕈碱型乙酰胆碱受体介导。我们的结果提示了一种模型，其中强烈的胆碱能刺激触发编码转录因子c-Fos的基因的快速诱导。然后这种蛋白质对参与乙酰胆碱代谢的基因的长期活性介导选择性调节作用。
