Fitzsimons Helen L, Schwartz Silvia, Given Fiona M, Scott Maxwell J
Institute of Fundamental Sciences, Massey University, Palmerston North, New Zealand.
Department of Entomology, North Carolina State University, Raleigh, North Carolina, United States of America.
PLoS One. 2013 Dec 9;8(12):e83903. doi: 10.1371/journal.pone.0083903. eCollection 2013.
A growing body of research indicates that pharmacological inhibition of histone deacetylases (HDACs) correlates with enhancement of long-term memory and current research is concentrated on determining the roles that individual HDACs play in cognitive function. Here, we investigate the role of HDAC4 in long-term memory formation in Drosophila. We show that overexpression of HDAC4 in the adult mushroom body, an important structure for memory formation, resulted in a specific impairment in long-term courtship memory, but had no affect on short-term memory. Overexpression of an HDAC4 catalytic mutant also abolished LTM, suggesting a mode of action independent of catalytic activity. We found that overexpression of HDAC4 resulted in a redistribution of the transcription factor MEF2 from a relatively uniform distribution through the nucleus into punctate nuclear bodies, where it colocalized with HDAC4. As MEF2 has also been implicated in regulation of long-term memory, these data suggest that the repressive effects of HDAC4 on long-term memory may be through interaction with MEF2. In the same genetic background, we also found that RNAi-mediated knockdown of HDAC4 impairs long-term memory, therefore we demonstrate that HDAC4 is not only a repressor of long-term memory, but also modulates normal memory formation.
越来越多的研究表明，对组蛋白脱乙酰酶（HDACs）的药理学抑制与长期记忆的增强相关，并且当前的研究集中在确定各个HDAC在认知功能中所起的作用。在这里，我们研究了HDAC4在果蝇长期记忆形成中的作用。我们表明，在成体蘑菇体（记忆形成的重要结构）中过表达HDAC4，会导致长期求偶记忆出现特定损伤，但对短期记忆没有影响。HDAC4催化突变体的过表达也消除了长期记忆，这表明其作用方式独立于催化活性。我们发现，HDAC4的过表达导致转录因子MEF2从相对均匀地分布于细胞核重新分布到点状核体中，在那里它与HDAC4共定位。由于MEF2也与长期记忆的调节有关，这些数据表明HDAC4对长期记忆的抑制作用可能是通过与MEF2相互作用实现的。在相同的遗传背景下，我们还发现RNA干扰介导的HDAC4敲低会损害长期记忆，因此我们证明HDAC4不仅是长期记忆的抑制因子，还调节正常的记忆形成。
