Protein Phosphatase 1-Dependent Bidirectional Synaptic Plasticity Controls Ischemic Recovery in the Adult Brain

Hédou, Gaël; Koshibu, Kyoko; Farinelli, Mélissa; Kılıç, Ertuğrul; Gee, Christine E.; Kılıç, Ülkan; Baumgärtel, Karsten; Hermann, Dirk M.; Mansuy, Isabelle M.

doi:10.1523/jneurosci.4109-07.2008

Cited by 36 publications

(25 citation statements)

References 67 publications

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“…Indeed, coexpression of truncated PP1␣, which interacts with MEF2 but does not repress transcriptional activity, has no effect on hippocampal neuronal cell survival, which corresponds to the inability of tPP1␣ to repress MEF2-mediated transcriptional activity in these cells. Recent reports indicate that timing of PP1 activation and the type of neurotoxic stimulus are key determinants of a positive or negative role for PP1 in neuronal cell survival (18,26). This lends support to our finding that PP1␣-mediated repression of MEF2 may be a key determinant in regulation of neuronal survival.…”

Section: Discussionsupporting

confidence: 90%

Direct Interaction between Myocyte Enhancer Factor 2 (MEF2) and Protein Phosphatase 1α Represses MEF2-Dependent Gene Expression

Perry

Yang²,

Soora³

et al. 2009

Molecular and Cellular Biology

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The myocyte enhancer factor 2 (MEF2) transcription factors play important roles in neuronal, cardiac, and skeletal muscle tissues. MEF2 serves as a nuclear sensor, integrating signals from several signaling cascades through protein-protein interactions with kinases, chromatin remodeling factors, and other transcriptional regulators. Here, we report a novel interaction between the catalytic subunit of protein phosphatase 1␣ (PP1␣) and MEF2. Interaction occurs within the nucleus, and binding of PP1␣ to MEF2 potently represses MEF2-dependent transcription. The interaction utilizes uncharacterized domains in both PP1␣ and MEF2, and PP1␣ phosphatase activity is not obligatory for MEF2 repression. Moreover, a MEF2-PP1␣ regulatory complex leads to nuclear retention and recruitment of histone deacetylase 4 to MEF2 transcription complexes. PP1␣-mediated repression of MEF2 overrides the positive influence of calcineurin signaling, suggesting PP1␣ exerts a dominant level of control over MEF2 function. Indeed, PP1␣-mediated repression of MEF2 function interferes with the prosurvival effect of MEF2 in primary hippocampal neurons. The PP1␣-MEF2 interaction constitutes a potent locus of control for MEF2-dependent gene expression, having potentially important implications for neuronal cell survival, cardiac remodeling in disease, and terminal differentiation of vascular, cardiac, and skeletal muscle.The myocyte enhancer factor 2 (MEF2) transcription factors play important roles in T-cell selection, neuronal survival, and terminal differentiation of cardiac and skeletal muscle (3, 47). The MEF2 family proteins are encoded by four genes, MEF2A to -D, which demonstrate tissue-specific and temporally dependent developmental expression patterns. Expression and activity of MEF2 factors in both cardiac and skeletal muscle lineages are vital for activation and maintenance of genes representing the structural components of sarcomeric muscle. Gene-targeted ablation of MEF2A or MEF2C results in aberrant heart formation and premature death (32, 46), whereas loss of the single MEF2 gene in Drosophila melanogaster (Dmef2) results in complete loss of all muscle tissues (31). In neurons, MEF2 transcriptional activity plays a critical role for prevention of apoptosis due to neurocytotoxicity signals (1,5,20,37).The amino-terminal (NT) region of MEF2 transcription factors is composed of a highly conserved MADS (MCM1, agamous, deficiens, and serum response factor) domain, responsible for DNA binding to the consensus DNA binding element (T/C)TA(A/T) 4 TA(G/A), and the MEF2 domain, which is required for homo-and heterodimerization of MEF2 factors. The carboxyl terminus (CT) of all MEF2 factors is subject to alternative splicing, represents the target for several signal transduction pathways, and is required for transcriptional activation properties (3).MEF2 transcriptional activity is stimulated by the mitogenactivated protein kinase (MAPK) p38 signaling module (25, 50), Ca 2ϩ /calmodulin kinases (CaMKs) (52), extracellular signal-regulated kinase ...

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Section: Discussionsupporting

confidence: 90%

Direct Interaction between Myocyte Enhancer Factor 2 (MEF2) and Protein Phosphatase 1α Represses MEF2-Dependent Gene Expression

Perry

Yang²,

Soora³

et al. 2009

Molecular and Cellular Biology

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“…Previous studies have demonstrated that PP1 is a potent memory suppressor in adult mice (Genoux et al 2002) and a negative regulator of synaptic strength and synaptic plasticity in the hippocampus (Morishita et al 2001;Jouvenceau et al 2006;Hedou et al 2008). These functions of PP1 have been postulated to be mediated primarily by the cytoplasmic pool of PP1, in particular, by PP1 in synaptic terminals.…”

Section: Discussionmentioning

confidence: 99%

“…Protein phosphatase assays were carried out as previously described (Hedou et al 2008). Hippocampi were dissected and homogenized in 3.75 mM Tris-HCl (pH 7.4), 15 mM KCl, 3.75 mM NaCl, 250 mM EDTA, 50 mM EGTA, 30% (w/v) sucrose, 30% (v/v) glycerol, protease inhibitor cocktail (Sigma), 100 mM PMSF using a Dounce homogenizer, then centrifuged (1000g, 10 min).…”

Section: Protein Phosphatase Assaymentioning

confidence: 99%

Protein phosphatase 1-dependent transcriptional programs for long-term memory and plasticity

Gräff¹,

Koshibu²,

Jouvenceau³

et al. 2010

Learn. Mem.

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Gene transcription is essential for the establishment and the maintenance of long-term memory (LTM) and for long-lasting forms of synaptic plasticity. The molecular mechanisms that control gene transcription in neuronal cells are complex and recruit multiple signaling pathways in the cytoplasm and the nucleus. Protein kinases (PKs) and phosphatases (PPs) are important players in these mechanisms. Protein serine/threonine phosphatase 1 (PP1), in particular, was recently shown to be important for transcription-dependent memory by regulating chromatin remodeling. However, the impact of PP1 on gene transcription in adult neurons remains not fully delineated. Here, we demonstrate that the nuclear pool of PP1 is associated with transcriptional events involving molecular components of signaling cascades acting as positive and negative regulators of memory and brain plasticity. The data show that inhibiting this pool selectively in forebrain neurons improves memory performance, enhances long-term potentiation (LTP), and modulates gene transcription. These findings highlight an important role for PP1 in the regulation of gene transcription in LTM and synaptic plasticity in the adult brain.

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“…In this scenario, metaplasticity could promote functionally adaptive responses such as preventing potentiation of synaptic inputs to the point of excitoxicity. It is interesting to note in this context the considerable mechanistic overlap between neuroprotective preconditioning effects which prevent excitoxicity and metaplasticity [3,87,88].…”

Section: (A) Functional Implications Of Heterosynaptic Metaplasticitymentioning

confidence: 99%

Mechanisms of heterosynaptic metaplasticity

Hulme

Jones

Raymond³

et al. 2014

Phil. Trans. R. Soc. B

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Synaptic plasticity is fundamental to the neural processes underlying learning and memory. Interestingly, synaptic plasticity itself can be dynamically regulated by prior activity, in a process termed ‘metaplasticity’, which can be expressed both homosynaptically and heterosynaptically. Here, we focus on heterosynaptic metaplasticity, particularly long-range interactions between synapses spread across dendritic compartments, and review evidence for intra cellular versus inter cellular signalling pathways leading to this effect. Of particular interest is our previously reported finding that priming stimulation in stratum oriens of area CA1 in the hippocampal slice heterosynaptically inhibits subsequent long-term potentiation and facilitates long-term depression in stratum radiatum. As we have excluded the most likely intracellular signalling pathways that might mediate this long-range heterosynaptic effect, we consider the hypothesis that intercellular communication may be critically involved. This hypothesis is supported by the finding that extracellular ATP hydrolysis, and activation of adenosine A2 receptors are required to induce the metaplastic state. Moreover, delivery of the priming stimulation in stratum oriens elicited astrocytic calcium responses in stratum radiatum. Both the astrocytic responses and the metaplasticity were blocked by gap junction inhibitors. Taken together, these findings support a novel intercellular communication system, possibly involving astrocytes, being required for this type of heterosynaptic metaplasticity.

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Protein Phosphatase 1-Dependent Bidirectional Synaptic Plasticity Controls Ischemic Recovery in the Adult Brain

Cited by 36 publications

References 67 publications

Direct Interaction between Myocyte Enhancer Factor 2 (MEF2) and Protein Phosphatase 1α Represses MEF2-Dependent Gene Expression

Direct Interaction between Myocyte Enhancer Factor 2 (MEF2) and Protein Phosphatase 1α Represses MEF2-Dependent Gene Expression

Protein phosphatase 1-dependent transcriptional programs for long-term memory and plasticity

Mechanisms of heterosynaptic metaplasticity

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