The Nuclear Kinase Mitogen- and Stress-Activated Protein Kinase 1 Regulates Hippocampal Chromatin Remodeling in Memory Formation

Abstract

The extracellular signal-regulated kinase (ERK)/MAPK (mitogen-activated protein kinase) cascade has been established as a potent regulator of gene transcription in long-term memory formation, but the precise mechanisms of this regulation are poorly understood. ERK does not directly affect many of its nuclear targets, but rather must act through intermediary kinases. In this study, we investigated the role of mitogen-and stress-activated protein kinase 1 (MSK1), a nuclear kinase downstream of ERK, in chromatin remodeling during hippocampus-dependent memory formation. Mice lacking MSK1 show impaired Pavlovian fear conditioning and spatial learning, as well as a deficiency in histone phosphorylation and acetylation in the hippocampus after fear training. In addition, hippocampal slices from MSK1 knock-out mice exhibit a deficiency in both histone phosphorylation and acetylation after activation of the ERK pathway in vitro. In vivo injections of a histone deacetylase inhibitor, sodium butyrate, fail to alleviate the fear conditioning deficit in MSK1 knock-out mice. Finally, MSK1 knock-out mice demonstrate a deficiency in cAMP response element-binding protein (CREB) phosphorylation after fear training, which persists after sodium butyrate injection. This suggests that CREB phosphorylation and histone acetylation represent parallel targets of MSK1 function. Our study identifies MSK1 as an important regulator of chromatin remodeling in long-term memory.

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.…”

Epigenetic regulation of memory: implications in human cognitive disorders

“…HDAC inhibitors (HDACi) increase histone acetylation by inhibition of the molecular machinery responsible for removing acetyl groups from histone proteins. Treatment of rats and mice with HDACi can improve memory in wild type animals in several learning paradigms, including contextual and cued fear conditioning (40,(47)(48)(49)(50)(51)(52)(53). Furthermore, mice with deletion of the Hdac2 gene showed enhanced LTM, in response to fear conditioning, while overexpression of Hdac2 in the mouse brain decreased LTM (47).…”