Elsevier

Brain Research

Volume 1394, 7 June 2011, Pages 33-39
Brain Research

Research Report
Regulation of S100B gene in rat hippocampal CA1 area during long term potentiation

https://doi.org/10.1016/j.brainres.2011.04.025Get rights and content

Abstract

In the present study we investigated the regulation of S100B expression during tetanization-induced hippocampal long term potentiation, one of the best characterized forms of synaptic plasticity. Tetanization resulted in time-dependent change in S100B gene expression and protein content in hippocampal CA1 area. We analyzed the promoter region of the rat S100B gene and identified response elements for the tumor suppressor p53. ChIP assay revealed that p53 could bind to putative p53-binding sites of the S100B promoter. The time-dependent recruitment of p53 to its putative binding sites in the S100B gene promoter paralleled the time-course change of S100B mRNA and protein levels. Thus, these results strongly support the view that S100B gene may be a target of p53. Moreover, we demonstrated that the increase of S100B protein content was accompanied with the decrease of p53 protein content, and it seems that the decrease is regulated on post-translational level. Thus, our results may help to understand the physiological function of the p53–S100B–p53 loop in the process of synaptic plasticity.

Research Highlights

► Long term potentiation results in time-dependent change in S100B gene expression and protein content in hippocampal CA1 area. ► The time-dependent recruitment of p53 to its putative binding sites in the S100B gene promoter paralleled the time-course change of S100B mRNA and protein levels. S100B gene may be a target of p53. ► The increase of S100B protein content is accompanied with the decrease of p53 protein content, and it seems that the decrease is regulated on post-translational level.

Introduction

Synaptic plasticity is a fundamental property of the nervous system. One of the best characterized forms of synaptic plasticity is hippocampal long term potentiation (LTP). The late phase of LTP is known to be dependent on mRNA and protein synthesis during brief time after stimulus (Reymann and Frey, 2007). A lot of genes such as transcription factors, growth factors and enzymes involved in signal transduction have been identified that are rapidly induced in association with LTP (Park et al., 2006). Recently we showed that tetanization-induced LTP in CA1 of rat hippocampus was attended by a time-dependent change of S100B gene expression (Lisachev et al., 2010). S100B mRNA level increased 30 min after tetanization, and then returned to control level 2 h after tetanization, whilst a low frequency stimulation did not change S100B mRNA level. This observation suggests a close association of the mechanisms of S100B gene expression activation with the mechanisms of LTP.

S100B gene encodes a member of EF-hand calcium binding protein, in central nervous system expressed mainly by astrocytes (Sorci et al., 2010). Interestingly, S100B was found to increase after brain damages, as well as in some psychiatric disorders (Rothermundt et al., 2001). Moreover, overexpression of S100B was shown in the brain of patients with Down's syndrome and Alzheimer's disease (Griffin et al., 1989, Mrak and Griffin, 2001).

Many cellular stimulations such as cell contact, hypoxia, UV, and other are able to stimulate S100B expression (Scotto et al., 1998). Many of these stimulations are known to activate tumor suppressor p53 protein. p53 plays a pivotal role in cell cycle arrest and apoptosis (Levine, 1997). p53 is highly regulated by numerous post-translational modifications and via interactions with other proteins (Laptenko and Prives, 2006). In fact, several members of the S100 family, including S100B, have been shown to interact with p53 in calcium-dependent manner and change its cellular level, transcriptional activity, and p53-dependent apoptosis (Wilder et al., 2006).

Biological functions of p53 are mainly mediated through the activation of downstream target genes (Laptenko and Prives, 2006). As transcription factor, p53 binds to its concensus DNA-binding specific sequence (two copies of the 10 bp motif 5′-PuPuPuC(A/T)(T/A)GPyPyPy-3′, separated by 0–13 bp) (el-Deiry et al., 1992) and activates the transcription of numerous target genes including a cyclin-dependent kinase inhibitor p21, cell cycle control proteins, genes involved in apoptosis, and other (Laptenko and Prives, 2006). p53 also activates the transcription of human S100 genes, including S100B, S100A2, and S100A9, in cancer cells (Li et al., 2009, Lin et al., 2004, Tan et al., 1999).

In this study we have hypothesized that activation of p53 following tetanization contributes to a rapid increase in S100B gene expression in rat hippocampal CA1 area.

Section snippets

Results

Time-dependent change in S100B expression was investigated in rat hippocampal CA1 area after tetanization. As was described previously (Lisachev et al., 2010), used tetanization protocol induces long term potentiation lasting at least 3 h (Fig. 1B). Tetanization resulted in time-dependent change in S100B gene expression (Fig. 2A). A 1.4-fold increase in S100B mRNA level was observed within 10 min after tetanization. S100B mRNA level reached a maximum in 20 min after tetanization (2.8-fold above

Discussion

Numerous previous studies characterized genes that respond to LTP, especially IEGs. Recently we found that S100B gene expression was significantly regulated in rat hippocampal CA1 area after tetanization in a time-dependent manner (Lisachev et al., 2010). The present study was focused on the regulatory mechanism of S100B expression after tetanization. A time-course real-time PCR analysis showed that S100B mRNA rapidly increased within 10 min after tetanization with the maximum observed at 20 min.

Experimental animals

Male Wistar rats (180–220 g) were supplied by the Institute of Cytology and Genetics SB RAS (Novosibirsk, Russia). Animals were acclimated for 1 week and were allowed free access to food and water. All experimental procedures were approved by the Animal Care Committee of the Institute of Molecular Biology and Biophysics SB RAMS.

Hippocampal slice preparation and tetanization

Animals were decapitated, and the brain was rapidly removed and placed in ice-cold oxygenated (95% O2, 5% CO2) artificial cerebrospinal fluid (aCSF): 126 mM NaCl, 4 mM KCl,

Acknowledgment

This work was supported by RFBR grant No. 09-04-00200-a.

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