The histone deacetylase HDAC4 regulates long-term memory in Drosophila

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Drosophila Proteins / biosynthesis*
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism
  • Drosophila melanogaster
  • Gene Expression Regulation, Enzymologic / physiology*
  • Gene Knockdown Techniques
  • Histone Deacetylases / biosynthesis*
  • Histone Deacetylases / genetics
  • Memory, Long-Term / physiology*
  • Mushroom Bodies / cytology
  • Mushroom Bodies / enzymology*
  • Myogenic Regulatory Factors / genetics
  • Myogenic Regulatory Factors / metabolism


  • Drosophila Proteins
  • Mef2 protein, Drosophila
  • Myogenic Regulatory Factors
  • HDAC4 protein, Drosophila
  • Histone Deacetylases

Grant support

This research was conducted during the tenure of a Postdoctoral Fellowship of the New Zealand Foundation for Research, Science and Technology (now known as the Ministry of Business, Innovation and Employment to HLF, a Sir Charles Hercus Health Research Fellowship of the Health Research Council of New Zealand ( to HLF, and a Massey University Research Fund ( grant to HLF. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.