Regulation of Histone Acetylation during Memory Formation in the Hippocampus

Formation of long term memory begins with the activation of many disparate signaling pathways that ultimately impinge on the cellular mechanisms regulating gene expression. We investigated whether mechanisms regulating chromatin structure were activated during the early stages of long term memory fo...

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Bibliographic Details
Published in:The Journal of biological chemistry 2004-09, Vol.279 (39), p.40545-40559
Main Authors: Levenson, Jonathan M., O'Riordan, Kenneth J., Brown, Karen D., Trinh, Mimi A., Molfese, David L., Sweatt, J. David
Format: Article
Language:English
Subjects:
Acetylation
Animals
Behavior, Animal
Blotting, Western
Chromatin - metabolism
Cyclic AMP-Dependent Protein Kinases - metabolism
Electrophysiology
Fear
Heterochromatin - metabolism
Hippocampus - metabolism
Hippocampus - physiology
Histones - metabolism
Hydroxamic Acids - pharmacology
Male
Memory
Mitogen-Activated Protein Kinases - metabolism
Models, Biological
Models, Genetic
N-Methylaspartate - metabolism
Phosphorylation
Protein Kinase C - metabolism
Rats
Rats, Sprague-Dawley
Receptors, N-Methyl-D-Aspartate - metabolism
Sodium Oxybate - pharmacology
Time Factors
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Summary:Formation of long term memory begins with the activation of many disparate signaling pathways that ultimately impinge on the cellular mechanisms regulating gene expression. We investigated whether mechanisms regulating chromatin structure were activated during the early stages of long term memory formation in the hippocampus. Specifically, we investigated hippocampal histone acetylation during the initial stages of consolidation of long term association memories in a contextual fear conditioning paradigm. Acetylation of histone H3 in area CA1 of the hippocampus was regulated in contextual fear conditioning, an effect dependent on activation of N-methyl-d-aspartic acid (NMDA) receptors and ERK, and blocked using a behavioral latent inhibition paradigm. Activation of NMDA receptors in area CA1 in vitro increased acetylation of histone H3, and this effect was blocked by inhibition of ERK signaling. Moreover, activation of ERK in area CA1 in vitro through either the protein kinase C or protein kinase A pathways, biochemical events known to be involved in long term memory formation, also increased histone H3 acetylation. Furthermore, we observed that elevating levels of histone acetylation through the use of the histone deacetylase inhibitors trichostatin A or sodium butyrate enhanced induction of long term potentiation at Schaffer-collateral synapses in area CA1 of the hippocampus, a candidate mechanism contributing to long term memory formation in vivo. In concert with our findings in vitro, injection of animals with sodium butyrate prior to contextual fear conditioning enhanced formation of long term memory. These results indicate that histone-associated heterochromatin undergoes changes in structure during the formation of long term memory. Mimicking memory-associated changes in heterochromatin enhances a cellular process thought to underlie long term memory formation, hippocampal long term potentiation, and memory formation itself.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M402229200