Brain Research Institute, Medical Faculty of the University Zürich and Department of Biology of the Swiss Federal Institute of Technology, CH-8057 Zürich, Switzerland.
Neuroscience. 2011 Jan 26;173:30-6. doi: 10.1016/j.neuroscience.2010.11.023. Epub 2010 Nov 18.
Complex brain diseases and neurological disorders in human generally result from the disturbance of multiple genes and signaling pathways. These disturbances may derive from mutations, deletions, translocations or rearrangements of specific gene(s). However, over the past years, it has become clear that such disturbances may also derive from alterations in the epigenome affecting several genes simultaneously. Our work recently demonstrated that epigenetic mechanisms in the adult brain are in part regulated by protein phosphatase 1 (PP1), a protein Ser/Thr phosphatase that negatively regulates hippocampus-dependent long-term memory (LTM) and synaptic plasticity. PP1 is abundant in brain structures involved in emotional processing like the amygdala, it may therefore be involved in the regulation of fear memory, a form of memory related to post-traumatic stress disorder (PTSD) in human. Here, we demonstrate that PP1 is a molecular suppressor of fear memory and synaptic plasticity in the amygdala that can control chromatin remodeling in neurons. We show that the selective inhibition of the nuclear pool of PP1 in amygdala neurons significantly alters posttranslational modifications (PTMs) of histones and the expression of several memory-associated genes. These alterations correlate with enhanced fear memory, and with an increase in long-term potentiation (LTP) that is transcription-dependent. Our results underscore the importance of nuclear PP1 in the amygdala as an epigenetic regulator of emotional memory, and the relevance of protein phosphatases as potential targets for therapeutic treatment of brain disorders like PTSD.
人类复杂的脑部疾病和神经紊乱通常是由多个基因和信号通路的紊乱引起的。这些紊乱可能源于特定基因的突变、缺失、易位或重排。然而，在过去的几年中，人们已经清楚地认识到，这种紊乱也可能源于影响多个基因的表观基因组改变。我们最近的研究表明，成年大脑中的表观遗传机制部分受到蛋白磷酸酶 1（PP1）的调控，PP1 是一种蛋白丝氨酸/苏氨酸磷酸酶，可负向调节海马依赖性长时记忆（LTM）和突触可塑性。PP1 在杏仁核等参与情绪处理的脑结构中含量丰富，因此可能参与了恐惧记忆的调节，恐惧记忆是与人类创伤后应激障碍（PTSD）相关的一种记忆形式。在这里，我们证明 PP1 是杏仁核中恐惧记忆和突触可塑性的分子抑制因子，可控制神经元中的染色质重塑。我们发现，选择性抑制杏仁核神经元中的核内 PP1 池会显著改变组蛋白的翻译后修饰（PTMs）和几种与记忆相关基因的表达。这些改变与增强的恐惧记忆相关，并且与依赖转录的长时程增强（LTP）增加相关。我们的研究结果强调了核内 PP1 作为情感记忆的表观遗传调节剂在杏仁核中的重要性，以及蛋白磷酸酶作为 PTSD 等脑部疾病潜在治疗靶点的相关性。
