Protein phosphatase 1 is a molecular constraint on learning and memory

Genoux, David; Haditsch, Ursula; Knobloch, Marlen; Michalon, Aubin; Storm, Daniel R.; Mansuy, Isabelle M.

doi:10.1038/nature00928

Cited by 427 publications

(367 citation statements)

References 27 publications

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“…Repression of PP1c may result in several effects on the intracellular signal transduction level; for example, inhibition of PP1c has been shown to increase phosphorylation of the a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid Cocaine-induced DNA methylation K Anier et al (AMPA) receptor subunit GluR1 and Ca2 + /calmodulindependent protein kinase II (Genoux et al, 2002). Reduced PP1 may have important effects for transcriptional regulation by CREB through the ability of PP1 to complex with HDAC.…”

Section: Discussionmentioning

confidence: 99%

DNA Methylation Regulates Cocaine-Induced Behavioral Sensitization in Mice

Anier

Malinovskaja

Aonurm-Helm

et al. 2010

Neuropsychopharmacol

187

170

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The behavioral sensitization produced by repeated cocaine treatment represents the neural adaptations underlying some of the features of addiction in humans. Cocaine administrations induce neural adaptations through regulation of gene expression. Several studies suggest that epigenetic modifications, including DNA methylation, are the critical regulators of gene expression in the adult central nervous system. DNA methylation is catalyzed by DNA methyltransferases (DNMTs) and consequent promoter region hypermethylation is associated with transcriptional silencing. In this study a potential role for DNA methylation in a cocaine-induced behavioral sensitization model in mice was explored. We report that acute cocaine treatment caused an upregulation of DNMT3A and DNMT3B gene expression in the nucleus accumbens (NAc). Using methylated DNA immunoprecipitation, DNA bisulfite modification, and chromatin immunoprecipitation assays, we observed that cocaine treatment resulted in DNA hypermethylation and increased binding of methyl CpG binding protein 2 (MeCP2) at the protein phosphatase-1 catalytic subunit (PP1c) promoter. These changes are associated with transcriptional downregulation of PP1c in NAc. In contrast, acute and repeated cocaine administrations induced hypomethylation and decreased binding of MeCP2 at the fosB promoter, and these are associated with transcriptional upregulation of fosB in NAc. We also found that pharmacological inhibition of DNMT by zebularine treatment decreased cocaine-induced DNA hypermethylation at the PP1c promoter and attenuated PP1c mRNA downregulation in NAc. Finally, zebularine and cocaine co-treatment delayed the development of cocaine-induced behavioral sensitization. Together, these results suggest that dynamic changes of DNA methylation may be an important gene regulation mechanism underlying cocaine-induced behavioral sensitization.

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Section: Discussionmentioning

confidence: 99%

DNA Methylation Regulates Cocaine-Induced Behavioral Sensitization in Mice

Anier

Malinovskaja

Aonurm-Helm

et al. 2010

Neuropsychopharmacol

187

170

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“…To further examine the relevance of histones marks for memory consolidation, we took advantage of a recently developed transgenic mouse model 22 , in which memory is enhanced by inhibition of the chromatin regulator and memory suppressor PP1 23 . In this model, PP1 is selectively inhibited in forebrain neurons, in particular in the hippocampus and PFC ( Supplementary Fig.…”

Section: Hippocampal Histone Ptms Are Induced Rapidly But Transientlymentioning

confidence: 99%

“…To confirm this hypothesis in physiologically relevant conditions, we used an intensive training protocol (15 min instead of 5 min intertrial intervals) known to elicit robust long-term memory 23 , and trained a new batch of control mice (Fig. 3a).…”

Section: Hippocampal Histone Ptms Are Induced Rapidly But Transientlymentioning

confidence: 99%

Dynamic histone marks in the hippocampus and cortex facilitate memory consolidation

et al. 2012

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memory consolidation requires a timely controlled interplay between the hippocampus, a brain region important for memory formation, and the cortex, a region recruited for memory storage. Here we show that memory consolidation is associated with specific epigenetic modifications on histone proteins that have a distinct dynamic in these brain areas. While in the hippocampus, histone post-translational modifications (PTms) are rapidly and transiently activated after learning, in the cortex they are induced with delay but persist over time. When these histone PTms are increased in vivo by transgenic intervention or intense training, they facilitate memory consolidation. Conversely, when they are pharmacologically blocked, memory consolidation is impaired. These histone PTms are further associated with the expression of the immediate early gene zif268, a transcription factor that favours memory consolidation. These findings reveal the spatiotemporal dynamics of histone marks during memory consolidation, and demonstrate their inherent 'mnemonic' property.

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“…B (2003) memory in a two-object task when an inhibitor of CREB, cAMP-responsive element modulator and ATF1 isoforms is expressed in the CA1 area of the hippocampus (Pittenger et al 2002). Interestingly, genetic inhibition of calcineurin phosphatase activity (Malleret et al 2001) or of protein phosphatase 1 improves object recognition memory and in the latter case, the mutation also increased training-induced activation of CRE-mediated gene transcription (Genoux et al 2002).…”

Section: Requirement Of the Ieg Zif268 For Recognition Memorymentioning

confidence: 99%

MAPK, CREB andzif268are all required for the consolidation of recognition memory

Bozon

Kelly

Josselyn

et al. 2003

Phil. Trans. R. Soc. Lond. B

280

211

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There has been nearly a century of interest in the idea that encoding and storage of information in the brain requires changes in the efficacy of synaptic connections between neurons that are activated during learning. Recent research into the molecular mechanisms of long-term potentiation (LTP) has brought about new knowledge that has provided valuable insights into the neural mechanisms of memory storage. The evidence indicates that rapid activation of the genetic machinery can be a key mechanism underlying the enduring modification of neural networks required for the stability of memories. In recent years, a wealth of experimental data has highlighted the importance of mitogen-activated protein kinase/ extracellular signal-regulated kinase (MAPK/ERK) signalling in the regulation of gene transcription in neurons. Here, we briefly review experiments that have shown MAPK/ERK, cAMP response elementbinding protein (CREB) and the immediate early gene (IEG) zif268 are essential components of a signalling cascade required for the expression of late phase LTP and of certain forms of long-term memory. We also present experiments in which we have assessed the role of these three molecules in recognition memory. We show that pharmacological blockade of MAPK/ERK phosphorylation, functional inactivation of CREB in an inducible transgenic mouse and inactivation of zif268 in a mutant mouse result in a similar deficit in long-term recognition memory. In the continuing debate about the role of LTP mechanisms in memory, these findings provide an important complement to the suggestion that synaptic changes brought about by LTP and memory consolidation and storage share, at least in part, common underlying molecular mechanisms.

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Protein phosphatase 1 is a molecular constraint on learning and memory

Cited by 427 publications

References 27 publications

DNA Methylation Regulates Cocaine-Induced Behavioral Sensitization in Mice

DNA Methylation Regulates Cocaine-Induced Behavioral Sensitization in Mice

Dynamic histone marks in the hippocampus and cortex facilitate memory consolidation

MAPK, CREB andzif268are all required for the consolidation of recognition memory

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