HDAC4控制了一种转录程序,该程序对突触可塑性和记忆力至关重要
Richard Sando1, Natalia Gounko2, Simon Pieraut2
1Department of Cell Biology, The Scripps Research Institute, La Jolla, CA 92037, USA; The Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA 92037, USA; The Kellogg School of Science and Technology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Cell
|November 13, 2012
概括
希斯脱乙酶4 (HDAC4) 调节突触可塑性和记忆力的基因. 一种与精神障碍相关的突变形式损害了大脑功能,突出显示了HDAC4.
科学领域:
- 神经科学是一个神经科学.
- 分子生物学分子生物学
- 遗传学 是一个遗传学.
背景情况:
- 神经元活动塑造基因表达,对大脑发育和功能至关重要.
- 将神经元活动与基因调节联系起来的分子机制尚未完全理解.
- 基因组脱乙酶 (HDACs) 是关键的表观遗传调节剂,涉及到各种细胞过程.
研究的目的:
- 为了研究基因组脱乙酶4 (HDAC4) 在神经元可塑性和记忆中的作用.
- 阐明HDAC4影响突触功能的分子机制.
- 为了检查与精神障碍相关的特定HDAC4等位基因对大脑功能的影响.
主要方法:
- 研究了HDAC4在反应神经元刺激时在细胞核和细胞质之间穿.
- 研究了HDAC4与染色质的相互作用及其通过NMDA受体的调节.
- 分析了HDAC4的转录标及其在突触组件中的作用.
- 使用了一种携带模仿精神障碍相关等位基因突变的小鼠模型.
主要成果:
- HDAC4核导入和染色体协会受到NMDA受体活性的负调节.
- 核HDAC4抑制了对中枢突触形成和功能至关重要的基因,影响了突触强度.
- 一个截断的,功能增强的HDAC4抑制剂,与精神障碍相关,破坏了转录和突触传输.
- 具有突变HDAC4等位基因的小鼠在神经传递,空间学习和记忆方面表现出缺陷.
结论:
- HDAC4是神经元活动与突触可塑性和记忆的调节之间的关键分子联系.
- 功能障碍的HDAC4,特别是与精神障碍相关的突变形式,导致显著的认知和突触缺陷.
- 这些发现揭示了经验依赖的大脑可塑性的关键机制以及HDAC4在认知功能中的特定生物学作用.
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