Spatial memory consolidation is associated with induction of several lysine-acetyltransferase (histone acetyltransferase) expression levels and H2B/H4 acetylation-dependent transcriptional events in the rat hippocampus.
Numerous genetic studies have shown that the CREB-binding protein (CBP) is an essential component of long-term memory formation, through its histone acetyltransferase (HAT) function. E1A-binding protein p300 and p300/CBP-associated factor (PCAF) have also recently been involved in memory formation. By contrast, only a few studies have reported on acetylation modifications during memory formation, and it remains unclear as to how the system is regulated during this dynamic phase. We investigated acetylation-dependent events and the expression profiles of these HATs during a hippocampus-dependent task taxing spatial reference memory in the Morris water maze. We found a specific increase in H2B and H4 acetylation in the rat dorsal hippocampus, while spatial memory was being consolidated. This increase correlated with the degree of specific acetylated histones enrichment on some memory/plasticity-related gene promoters. Overall, a global increase in HAT activity was measured during this memory consolidation phase, together with a global increase of CBP, p300, and PCAF expression. Interestingly, these regulations were altered in a model of hippocampal denervation disrupting spatial memory consolidation, making it impossible for the hippocampus to recruit the CBP pathway (CBP regulation and acetylated-H2B-dependent transcription). CBP has long been thought to be present in limited concentrations in the cells. These results show, for the first time, that CBP, p300, and PCAF are dynamically modulated during the establishment of a spatial memory and are likely to contribute to the induction of a specific epigenetic tagging of the genome for hippocampus-dependent (spatial) memory consolidation. These findings suggest the use of HAT-activating molecules in new therapeutic strategies of pathological aging, Alzheimer's disease, and other neurodegenerative disorders.
Bousiges
Olivier
O
Inserm, U692, Laboratoire de Signalisations Moléculaires et Neurodégénérescence, Strasbourg, France.
Vasconcelos
Anne Pereira de
AP
Neidl
Romain
R
Cosquer
Brigitte
B
Herbeaux
Karine
K
Panteleeva
Irina
I
Loeffler
Jean-Philippe
JP
Cassel
Jean-Christophe
JC
Boutillier
Anne-Laurence
AL
D000107:Acetylation; D000818:Animals; D050882:CREB-Binding Protein / Q000096:biosynthesis; D050881:E1A-Associated p300 Protein / Q000096:biosynthesis; D005786:Gene Expression Regulation / Q000502:physiology*; D006624:Hippocampus / Q000378:metabolism* / Q000502:physiology*; D051548:Histone Acetyltransferases / Q000096:biosynthesis*; D006657:Histones / Q000378:metabolism*; D008297:Male; D018782:Maze Learning / Q000502:physiology; D008568:Memory / Q000502:physiology*; D051381:Rats; D020318:Rats, Long-Evans; D013037:Spatial Behavior / Q000502:physiology*; D050880:p300-CBP Transcription Factors / Q000096:biosynthesis; D000099224:p300-CBP-Associated Factor
D050882:CREB-Binding Protein; D050881:E1A-Associated p300 Protein; D051548:Histone Acetyltransferases; D006657:Histones; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor
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