改写Science十大科学突破 女科学家再发Nature文章

　　

生物通报道：2007年生命科学领域最受关注的莫过于人类基因组差异研究和皮肤细胞培养胚胎干细胞的研究，这两项研究都荣登了2007年Science杂志评选的十大科学突破。除了这两项研究，2007年神经科学方面也获得了一项重要的突破：发现人类大脑重要记忆中心。这些研究成果中有一项就是确定了影响阿兹海默症恢复长时程基因和学习能力的基因。

然而事隔2年，来自霍德华休斯医学院，MIT Picower学习和记忆研究中心（Picower Institute for Learning and Memory）的研究人员发现与突触可塑性、记忆形成及跟记忆相关的树状结构变化的诱导成逆相关不是HDAC1，而是HDAC2基因。

领导这一研究的是国际著名神经学科学家的蔡理慧（Li-Huei Tsai）博士，其研究小组之前的研究表明由组蛋白乙酰化造成的染色质修饰是学习和记忆过程的一个促动因素，给脑部受损的小鼠使用HDAC抑制剂，能够使小鼠恢复失去的记忆。

研究人员发现HDAC抑制剂能大量地提升树突的生长并且增加突触发生(创造神经细胞之间的联系)。这个过程可能会增强记忆或者允许小鼠通过重新修复受损的神经回路来重新获得失去的记忆。尽管科学家仍然不能准确地知道外部的控制如何影响记忆，但理论认为，锻炼、视觉强化或者药物放松了DNA等可触发与神经可塑性相关的基因表达。基因表达的增加能触发新的神经联系，从而巩固神经回路。

除此之外，研究人员还发现HDAC2与被认为在弹性和记忆中所涉及的基因也存在特异性关联，而HDAC1则没有这种关联性。这些发现说明以HDAC2（而不是HDAC1）为目标的药物在与记忆丧失相关的人类疾病的治疗中也许会更有价值。

原文摘要：

HDAC2 negatively regulates memory formation and synaptic plasticity

Ji-Song Guan1,2,3,9, Stephen J. Haggarty3,4,9, Emanuela Giacometti5,6,9, Jan-Hermen Dannenberg7,9,10, Nadine Joseph1,2,3, Jun Gao1,2, Thomas J. F. Nieland3, Ying Zhou1,2, Xinyu Wang1,2, Ralph Mazitschek3,8, James E. Bradner3, Ronald A. DePinho7, Rudolf Jaenisch5,6 & Li-Huei Tsai1,2

Chromatin modifications, especially histone-tail acetylation, have been implicated in memory formation. Increased histone-tail acetylation induced by inhibitors of histone deacetylases (HDACis) facilitates learning and memory in wild-type mice as well as in mouse models of neurodegeneration. Harnessing the therapeutic potential of HDACis requires knowledge of the specific HDAC family member(s) linked to cognitive enhancement. Here we show that neuron-specific overexpression of HDAC2, but not that of HDAC1, decreased dendritic spine density, synapse number, synaptic plasticity and memory formation. Conversely, Hdac2 deficiency resulted in increased synapse number and memory facilitation, similar to chronic treatment with HDACis in mice. Notably, reduced synapse number and learning impairment of HDAC2-overexpressing mice were ameliorated by chronic treatment with HDACis. Correspondingly, treatment with HDACis failed to further facilitate memory formation in Hdac2-deficient mice. Furthermore, analysis of promoter occupancy revealed an association of HDAC2 with the promoters of genes implicated in synaptic plasticity and memory formation. Taken together, our results suggest that HDAC2 functions in modulating synaptic plasticity and long-lasting changes of neural circuits, which in turn negatively regulates learning and memory. These observations encourage the development and testing of HDAC2-selective inhibitors for human diseases associated with memory impairment.