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以前的研究工作已经识别出，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，研究方法是，对啮齿类模型施用组蛋白脱乙酰酶（HDAC）抑制因子。 现在，用小鼠进行的实验表明，是HDAC2、而不是HDAC1的神经元水平与突触可塑性、记忆形成及跟记忆相关的树状结构变化的诱导成逆相关。另外，HDAC2专门与被认为在弹性和记忆中所涉及的基因相关联，而HDAC1则不。这些发现提出一个可能性：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有价值。 推荐原始出处： Nature 459, 55-60 (7 May 2009) | doi:10.1038/nature07925 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 Tsai1,2,3 1 Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, 2 Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA 3 Stanley Center for Psychiatric Research, Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA 4 Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02142, USA 5 Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA 6 Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA 7 Belfer Institute for Applied Cancer Science, Departments of Medical Oncology, Medicine and Genetics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA 8 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115, USA 9 These authors contributed equally to this work. 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. (责任编辑：Doctor001) |
