Regulation of Histone Acetylation during Memory Formation in the Hippocampus

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.

Dynamic histone marks in the hippocampus and cortex facilitate memory consolidation

“…The data also show that these marks occur at the zif268 promoter and correlate with a shift of zif268 expression from the hippocampus to the PFC as the memory matures, suggesting an important functional role of these histone PTMs in memory consolidation. The results are in line with several recent findings showing that enhancing histone acetylation favours memory, including object 13,31 , fear 10,12,14,15,17,[32][33][34] , spatial 13,34 and taste 19,35 memory. They significantly extend these findings by showing that in addition to histone acetylation, histone phosphorylation and methylation (on H3K36) are activated in a temporally and spatially regulated manner during memory consolidation in both the hippocampus and the cortex.…”

“…2a-c). These results suggest a rapid activation of histone PTMs in the hippocampus, consistent with previous reports showing that histone phosphorylation and acetylation are increased shortly after fear conditioning 10,12,15 . Bonferroni post-hoc tests for the effect of treatment (control or transgenic) at individual time points following two-way AnoVAs with treatment (control and transgenic) and time (HABIT., sHoRT-TERm, RECEnT and REmoTE) as factors; *P < 0.05, **P < 0.01, ***P < 0.001. number of animals used for hippocampal samples: control (Con), HABIT., n = 13; sHoRT-TERm, n = 9; RECEnT, n = 8; REmoTE, n = 8; transgenic, HABIT., n = 10; sHoRT-TERm, n = 8; RECEnT, n = 8; REmoTE, n = 8; for PFC samples: Con, HABIT., n = 5; sHoRT-TERm, n = 5; RECEnT, n = 6; REmoTE, n = 6; transgenic, HABIT., n = 6 for sHoRT-TERm, RECEnT and REmoTE.…”

“…2a-d). These results indicate that a concomitant increase in pH3S10 and AcH3K14 in the hippocampus is associated with object memory formation in the transgenic mice, consistent with the reported role of these PTMs in fear memory 10,12,15 . Importantly, the data further suggest a dissociation between histone PTMs in the hippocampus and remote memory, because remote memory was improved after 7 days in the transgenic animals despite no apparent change in hippocampal PTMs compared with untrained mice.…”

“…We focused on PTMs previously associated with the formation of longterm associative memory 10,[12][13][14][15]19 , specifically phosphorylation of S10, acetylation of K14 and trimethylation of K36 on histone 3 (H3), and acetylation of K5 on H4. As the formation and storage of object memory depend on a temporally regulated interplay between hippocampal and cortical areas, in particular the PFC 20,21 , we postulated that PTMs occur in both brain regions but may be differentially regulated over time.…”

“…Over the past years, changes in gene expression during memory formation have been shown to be associated with epigenetic processes, in particular post-translational modifications (PTMs) of histone proteins and DNA methylation [9][10][11] . For histones, several PTMs have been unequivocally linked to memory formation and storage, in particular, phosphorylation of histone (H) 3 serine (S) 10 (refs 12-14); acetylation of H2B lysine (K) 5, H3K9, H3K14, H4K5 and H4K12 (refs 10,12-17); and methylation of H3K36 (ref.…”