Mulkey, R. M., Endo, S., Shenolikar, S. & Malenka, R. C. Involvement of a calcineurin/inhibitor-1 phosphatase cascade in hippocampal long-term depression. Nature 369, 486-488

Department of Psychiatry, University of California, San Francisco 94143-0984.
Nature (Impact Factor: 41.46). 07/1994; 369(6480):486-8. DOI: 10.1038/369486a0
Source: PubMed

ABSTRACT Long-term potentiation (LTP) is a synaptic mechanism thought to be involved in learning and memory. Long-term depression (LTD), an activity-dependent decrease in synaptic efficacy, may be an equally important mechanism which permits neural networks to store information more effectively. One form of LTD that has been observed in the hippocampus requires activation of postsynaptic NMDA (N-methyl-D-aspartate) receptors, a change in postsynaptic calcium concentration, and activation of postsynaptic serine/threonine protein phosphatase 1 (PP1) or 2A (PP2A). The mechanism by which PP1 or PP2A is regulated by synaptic activity is unclear because these protein phosphatases are not directly influenced by calcium concentration. LTD induction may require activation of a more complex protein phosphatase cascade consisting of the Ca2+/calmodulin-dependent protein phosphatase, calcineurin, its phosphoprotein substrate, inhibitor-1, and PP1. We tested this hypothesis using calcineurin inhibitors as well as different forms of inhibitor-1 loaded into postsynaptic cells. Our results suggest a signalling pathway in which calcineurin dephosphorylates and inactivates inhibitor-1. This in turn increases PP1 activity and contributes to the generation of LTD.

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Available from: Shogo Endo, Sep 29, 2015
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    • "Evidence suggested that phosphatases took part in this phenomenon (Anier et al., 2010). Phosphatases such as the Ca 2þ /calmodulin-dependent calcineurin and protein phosphatase (PP) 1/2A are negative regulators of both long-term potentiation and long-term memory storage (Malleret et al., 2001; Mauna et al., 2011; Mulkey et al., 1994; Woo and Nguyen, 2002). PP1 and PP2A play a key role in addiction reward and memory (Zachariou et al., 2002). "
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    ABSTRACT: Recent studies indicated that epigenetic modification, especially DNA methylation, play an important role in the persistence of addiction-related memory. 5-aza-2-deoxycytidine (5-aza), an inhibitor of DNA methyltransferases, was approved for clinical treatment. However, it is not clear whether 5-aza is involved in opiate addiction. In this study, using the morphine-induced conditioned place preference (mCPP) model in rats, we injected 5-aza into hippocampus (CA1) and prelimbic cortex (PL), and tested the behavioral consequences at various stages of consolidation, acquisition and retrieval. Moreover, to test whether protein phosphatase regulates the effects of 5-aza, protein phosphatase (PP) 1/2A inhibitor okadaic acid (OA) was infused before 5-aza injection. We found that 5-aza injection into CA1 but not into PL significantly attenuated the consolidation and acquisition of mCPP, however, the inhibition of DNA methylation in PL but not in CA1 enhanced the retrieval of mCPP. All these behavioral effects were absent when OA was infused before 5-aza injection. These findings suggest that 5-aza interfere opiate-related memory, and protein phosphatase plays an important role in this process.
    Neuropharmacology 08/2014; 86. DOI:10.1016/j.neuropharm.2014.08.005 · 5.11 Impact Factor
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    • "Long-term potentiation (LTP), a form of synaptic strengthening, is induced by a high rise in intracellular calcium concentration leading to activation of protein kinases. In contrast, long-term depression (LTD), a form of synaptic weakening, requires a moderate rise of intracellular calcium concentration that activates protein phosphatases including PP2B (calcineurin) and subsequently PP1 (Mulkey et al., 1993, 1994; Jouvenceau et al., 2003, 2006; Pi and Lisman, 2008). Once activated, PP1 dephosphorylates some of its targets in synaptic terminals (Morishita et al., 2001), in particular, post-synaptic NMDAR and AMPAR subunits, leading to NMDAR downregulation and AMPAR endocytosis, ultimately resulting in synaptic depression [for review, see (Mansuy and Shenolikar, 2006)]. "
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    ABSTRACT: Citation: Mirante O, Brandalise F, Bohacek J and Mansuy IM(2014) Distinct molecular components for thalamic-and cortical-dependent plasticity in the lateral amygdala. Front. Mol. Neurosci. 7:62. doi:10.3389/fnmol.2014.00062 /Journal/Abstract.aspx?s=702& name=molecular%20neuroscience& ART_DOI=10.3389/fnmol.2014.00062: /Journal/Abstract.aspx?s=702& name=molecular%20neuroscience&ART_DOI=10.3389 /fnmol.2014.00062 (If clicking on the link doesn't work, try copying and pasting it into your browser.) Copyright statement: © 2014 Mirante, Brandalise, Bohacek and Mansuy. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. This Provisional PDF corresponds to the article as it appeared upon acceptance, after rigorous peer-review. Fully formatted PDF and full text (HTML) versions will be made available soon.
    Frontiers in Molecular Neuroscience 06/2014; 7. DOI:10.3389/fnmol.2014.00062 · 4.08 Impact Factor
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    • "Central to NMDAR-mediated LTD production is activation by CaM of protein phosphatase 2B (PP2B, a.k.a. calcineurin), which activates PP1 by inactivating PPI1 (Mulkey et al., 1994). The CaM affinity of PP2B is higher than that of CaMKII or AC (Kim et al., 2010). "
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    ABSTRACT: The leading hypothesis on Alzheimer Disease (AD) is that it is caused by buildup of the peptide amyloid-β (Aβ), which initially causes dysregulation of synaptic plasticity and eventually causes destruction of synapses and neurons. Pharmacological efforts to limit Aβ buildup have proven ineffective, and this raises the twin challenges of understanding the adverse effects of Aβ on synapses and of suggesting pharmacological means to prevent them. The purpose of this paper is to initiate a computational approach to understanding the dysregulation by Aβ of synaptic plasticity and to offer suggestions whereby combinations of various chemical compounds could be arrayed against it. This data-driven approach confronts the complexity of synaptic plasticity by representing findings from the literature in a course-grained manner, and focuses on understanding the aggregate behavior of many molecular interactions. The same set of interactions is modeled by two different computer programs, each written using a different programming modality: one imperative, the other declarative. Both programs compute the same results over an extensive test battery, providing an essential crosscheck. Then the imperative program is used for the computationally intensive purpose of determining the effects on the model of every combination of ten different compounds, while the declarative program is used to analyze model behavior using temporal logic. Together these two model implementations offer new insights into the mechanisms by which Aβ dysregulates synaptic plasticity and suggest many drug combinations that potentially may reduce or prevent it.
    Frontiers in Pharmacology 05/2014; 5:85. DOI:10.3389/fphar.2014.00085 · 3.80 Impact Factor
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