The histone H3 lysine 9 methyltransferase G9a/GLP complex activity is required for long-term consolidation of spatial memory in mice

Neurobiol Learn Mem. 2021 Mar;179:107406. doi: 10.1016/j.nlm.2021.107406. Epub 2021 Feb 17.


The G9a/G9a-like protein (GLP) histone lysine dimethyltransferase complex and downstream histone H3 lysine 9 dimethylation (H3K9me2) repressive mark have recently emerged as key transcriptional regulators of gene expression programs necessary for long-term memory (LTM) formation in the dorsal hippocampus. However, the role for hippocampal G9a/GLP complex in mediating the consolidation of spatial LTM remains largely unknown. Using a water maze competition task in which both dorsal hippocampus-dependent spatial and striatum-dependent cue navigation strategies are effective to solve the maze, we found that pharmacological inhibition of G9a/GLP activity immediately after learning disrupts long-term consolidation of previously learned spatial information in male mice, hence producing cue bias on the competition test performed 24 h later. Importantly, the inhibition of hippocampal G9a/GLP did not disrupt short-term memory retention. Immunohistochemical analyses revealed increases in global levels of permissive histone H3K9 acetylation in the dorsal hippocampus and dorsal striatum at 1 h post-training, which persisted up to 24 h in the hippocampus. Conversely, H3K9me2 levels were either unchanged in the dorsal hippocampus or transiently decreased at 15 min post-training in the dorsal striatum. Finally, the inhibition of G9a/GLP activity further increased global levels of H3K9 acetylation while decreasing H3K9me2 in the hippocampus at 1 h post-training. However, both marks returned to vehicle control levels at 24 h. Together, these findings support the possibility that G9a/GLP in the dorsal hippocampus is required for the transcriptional switch from short-term to long-term spatial memory formation.

Keywords: Hippocampus; Histone methylation; Learning; Memory; Striatum.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Azepines / pharmacology
  • Corpus Striatum / drug effects
  • Corpus Striatum / metabolism*
  • Hippocampus / drug effects
  • Hippocampus / metabolism*
  • Histone Code
  • Histone-Lysine N-Methyltransferase / antagonists & inhibitors
  • Histone-Lysine N-Methyltransferase / physiology*
  • Male
  • Memory Consolidation / drug effects
  • Memory Consolidation / physiology*
  • Memory, Long-Term / drug effects
  • Memory, Long-Term / physiology*
  • Memory, Short-Term / drug effects
  • Memory, Short-Term / physiology*
  • Mice
  • Morris Water Maze Test
  • Quinazolines / pharmacology
  • Spatial Memory / drug effects
  • Spatial Memory / physiology*


  • Azepines
  • BIX 01294
  • Quinazolines
  • G9a protein, mouse
  • GLP protein, mouse
  • Histone-Lysine N-Methyltransferase