Abstract
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.
Highlights
Formation of long term memory requires several steps that end with regulation of gene expression
Our results demonstrate that the increase in P-ERK2 seen after fear conditioning requires the activation of N-methyl-D-aspartic acid (NMDA)-Rs and the upstream kinase in the ERK cascade, MEK
No change in the acetylation of histone H4 was observed by any of the above treatments (Fig. 3C). These results indicate that in area CA1 of the hippocampus, activation of NMDA1 receptors (NMDA-Rs) leads to increases in P-ERK2 and acetylation of histone H3, and that these events require the upstream kinase in the ERK cascade, MEK
Summary
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, increased histone H3 acetylation. Histone Acetylation in Long Term Memory Formation mals are exposed to phase-resetting light pulses, and chromatin structure is regulated in hippocampal neurons in response to activation of a variety of neurotransmitter pathways [16, 17]. Other studies have found regulation of chromatin structure around the ApC/EBP gene in Aplysia using a pharmacologic paradigm that triggers long term facilitation of neurotransmitter release at the sensory-motor neuron synapse in this species [20, 21] All of these studies indicate that chromatin structure is highly dynamic within the nervous system and suggest the possibility that chromatin structure itself might be recruited as a target of plasticity-associated signal transduction mechanisms. Taken together these observations implicate alterations in histone acetylation and, by extension, modulation of chromatin structure, in mammalian associative learning and long term memory formation
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