Abstract
Gene transcription and translation in the hippocampus is of critical importance in hippocampus-dependent memory formation, including during Morris water maze (MWM) learning. Previous work using gene deletion models has shown that the immediate-early genes (IEGs) c-Fos, Egr-1, and Arc are crucial for such learning. Recently, we reported that induction of IEGs in sparse dentate gyrus neurons requires ERK MAPK signaling and downstream formation of a distinct epigenetic histone mark (i.e., phospho-acetylated histone H3). Until now, this signaling, epigenetic and gene transcriptional pathway has not been comprehensively studied in the MWM model. Therefore, we conducted a detailed study of the phosphorylation of ERK1/2 and serine10 in histone H3 (H3S10p) and induction of IEGs in the hippocampus of MWM trained rats and matched controls. MWM training evoked consecutive waves of ERK1/2 phosphorylation and H3S10 phosphorylation, as well as c-Fos, Egr-1, and Arc induction in sparse hippocampal neurons. The observed effects were most pronounced in the dentate gyrus. A positive correlation was found between the average latency to find the platform and the number of H3S10p-positive dentate gyrus neurons. Furthermore, chromatin immuno-precipitation (ChIP) revealed a significantly increased association of phospho-acetylated histone H3 (H3K9ac-S10p) with the gene promoters of c-Fos and Egr-1, but not Arc, after MWM exposure compared with controls. Surprisingly, however, we found very little difference between IEG responses (regarding both protein and mRNA) in MWM-trained rats compared with matched swim controls. We conclude that exposure to the water maze evokes ERK MAPK activation, distinct epigenetic changes and IEG induction predominantly in sparse dentate gyrus neurons. It appears, however, that a specific role for IEGs in the learning aspect of MWM training may become apparent in downstream AP-1- and Egr-1-regulated (second wave) genes and Arc-dependent effector mechanisms.
Highlights
Hippocampus-dependent long-term memory formation is important for allowing adaptation and optimization of behavioral responses when similar circumstances are encountered again
Morris water maze (MWM) Training Leads to an Increase in the Phosphorylation of ERK1/2 and H3S10, and Induction of Immediate Early Genes in the Dentate Gyrus and cornu ammonis (CA) Regions The phosphorylation of ERK1/2 and H3S10, and the induction of c-Fos, early growth response 1 (Egr-1), and activity-regulated cytoskeletonassociated protein (Arc) was analyzed in the dentate gyrus (DG), CA1, and CA3 during 1 day of MWM training and up to 8 h later
The present study shows that exposure to the MWM leads to a rapid, transient phosphorylation of pERK1/2, a more protracted phosphorylation of H3S10, and transcription and translation of the immediate-early genes (IEGs) c-Fos, Egr-1, and Arc predominantly in sparse neurons of the DG
Summary
Hippocampus-dependent long-term memory formation is important for allowing adaptation and optimization of behavioral responses when similar circumstances are encountered again. Research into the molecular changes underlying hippocampus-dependent memory formation has identified an important role of the ERK MAPK (extracellular signalregulated kinase, mitogen-activated protein kinase) cascade and subsequent induction of the immediate-early genes (IEGs) FBJ murine osteosarcoma (c-Fos), early growth response 1 (Egr-1) and activity-regulated cytoskeletonassociated protein (Arc) (Atkins et al, 1998; Blum et al, 1999; Guzowski et al, 2001; Adams and Sweatt, 2002). Activation of the ERK MAPK cascade results in recruitment of nuclear kinases and transcription factors such as Elk-1 and CREB (Xia et al, 1996; Deak et al, 1998; Davis et al, 2000) as well as chromatin modifying enzymes [mitogen- and stress-activated kinase (MSK) and histone acetyl transferases (HATs)], leading to epigenetic changes within the chromatin in sparse dentate gyrus granule neurons (Chwang et al, 2007; Chandramohan et al, 2008; Reul et al, 2009, 2015; Gutierrez-Mecinas et al, 2011; Reul, 2014). The resultant phosphorylation of serine-10 and acetylation of lysine residues within histone H3 is thought to de-condense (open) the chromatin structure, potentially allowing transcription factors to bind to their responsive elements, leading to transcription of formerly silenced genes (Nowak and Corces, 2000; Cheung et al, 2000a,b; Reul et al, 2009; Mifsud et al, 2011; Trollope et al, 2012)
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