在近日出版的Neuron杂志上，美国科学家表示他们正在开发可选择性地提高大脑中的基因表达的新技术，藉以治疗精神疾病及神经系统疾病。许多证据显示，针对该机制的化合物能提高老鼠的学习和记忆能力。
过去的几年内，神经学家已经开始认识到表观遗传学的重要性。表观遗传指在大脑中，尤其是在记忆中改变基因表达而不改变DNA的分子过程，表观遗传关键的调节器之一是一群名为组蛋白脱乙酰基的酶（HDACs），它触发DNA将邻近的蛋白质缠绕得更紧，最终抑制基因表达。最近的研究已经证明，这些酶的抑制药物能加强正常老鼠和认知受到损害的老鼠的学习能力。
美国麻省理工学院的神经科学家蔡理慧（音译）团队去年证明，给脑部受损的老鼠使用HDAC抑制剂，能够使老鼠恢复失去的记忆。
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。美国国立药物滥用研究所表观遗传学项目主管约翰?斯特里说：“也许我们的大脑正在使用这些外部机制来让我们学习和记住事情，或者提供充足的可塑性来允许我们学习和调试。”
蔡理慧表示，已有充分证据证明，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老鼠通过重新修复受损的神经回路来重新获得失去的记忆。“我们相信记忆痕迹仍在那儿，但因神经回路遭到破坏，动物无法找回记忆。”（生物谷Bioon.com）
生物谷推荐原始出处：
Neuron, Volume 60, Issue 5, 803-817, 10 December 2008
Deregulation of HDAC1 by p25/Cdk5 in Neurotoxicity
Dohoon Kim1,2,Christopher L. Frank1,2,Matthew M. Dobbin1,Rachel K. Tsunemoto1,Weihong Tu3,Peter L. Peng3,Ji-Song Guan1,Byung-Hoon Lee1,Lily Y. Moy1,Paola Giusti1,Nisha Broodie1,Ralph Mazitschek4,Ivanna Delalle1,Stephen J. Haggarty4,5,Rachael L. Neve6,YouMing Lu3andLi-Huei Tsai1,4,,
1 Howard Hughes Medical Institute, Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
2 Division of Medical Sciences, Harvard Medical School, Boston, MA 02120, USA
3 Burnett College of Biomedical Sciences, University of Central Florida, Orlando, FL 32826, USA
4 Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard University, Cambridge, MA 02142, USA
5 Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA
6 Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA 02478, USA
Aberrant cell-cycle activity and DNA damage are emerging as important pathological components in various neurodegenerative conditions. However, their underlying mechanisms are poorly understood. Here, we show that deregulation of histone deacetylase 1 (HDAC1) activity by p25/Cdk5 induces aberrant cell-cycle activity and double-strand DNA breaks leading to neurotoxicity. In a transgenic model for neurodegeneration, p25/Cdk5 activity elicited cell-cycle activity and double-strand DNA breaks that preceded neuronal death. Inhibition of HDAC1 activity by p25/Cdk5 was identified as an underlying mechanism for these events, and HDAC1 gain of function provided potent protection against DNA damage and neurotoxicity in cultured neurons and an invivo model for ischemia. Our findings outline a pathological signaling pathway illustrating the importance of maintaining HDAC1 activity in the adult neuron. This pathway constitutes a molecular link between aberrant cell-cycle activity and DNA damage and isa potential target for therapeutics against diseases and conditions involving neuronal death.
