The Histone H3 Lysine 9 Methyltransferase G9a/GLP complex activity is required for long-term consolidation of spatial memory in mice
Neurobiology of Learning and Memory. 2021-02-01; : 107406
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Nicolay-Kritter K(1), Guillou JL(1), Mons N(2).
(1)Université de Bordeaux, France; Institut de Neurosciences Cognitives et Intégratives d’Aquitaine, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5287, 33615 Pessac, France.
(2)Université de Bordeaux, France; Institut de Neurosciences Cognitives et Intégratives d’Aquitaine, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5287, 33615 Pessac, France. Electronic address: .
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 24h 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 1h post-training, which persisted up to 24h in the hippocampus. Conversely, H3K9me2 levels were either unchanged in the dorsal hippocampus or transiently decreased at 15min 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 1h post-training. However, both marks returned to vehicle control levels at 24h. 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.