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


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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    • "In a previous publication, we had reported a caspase-and calcineurin-dependent pathological mechanism leading to lower levels of synaptic AMPAR in the hippocampus of these early symptomatic mice (D'Amelio et al, 2011). As both caspase and calcineurin have been implicated in hippocampal NMDAR-dependent LTD (Li et al, 2010b; Mulkey et al, 1994), they could also contribute to the enhanced LTD we further studied here. It will be important, in future studies, to identify the interplay between this previously identified pathological mechanism and the novel CORT-dependent mechanism we report now. "
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    ABSTRACT: The early phase of Alzheimer's disease (AD) is characterized by hippocampus-dependent memory deficits and impaired synaptic plasticity. Increasing evidence suggests that stress and dysregulation of the hypothalamo-pituitary-adrenal (HPA) axis, marked by elevated circulating glucocorticoids, are risk factors for AD onset. How these changes contribute to early hippocampal dysfunction remains unclear. Using an elaborated version of the object recognition task, we carefully monitored alterations in key components of episodic memory, the first type of memory altered in AD patients, in early symptomatic Tg2576 AD mice. We also combined biochemical and ex vivo electrophysiological analyses to reveal novel cellular and molecular dysregulations underpinning the onset of the pathology. We show that HPA axis circadian rhythm and feedback mechanisms, as well as episodic memory, are compromised in this early symptomatic phase, reminiscent of human AD pathology. The cognitive decline could be rescued by sub-chronic in vivo treatment with RU486, a glucocorticoid receptor antagonist. These observed phenotypes were paralleled by a specific enhancement of N-Methyl-D-aspartic acid receptor (NMDAR)-dependent LTD in CA1 pyramidal neurons, while LTP and metabotropic glutamate receptor-dependent LTD remain unchanged. NMDAR transmission was also enhanced. Finally, we show that, as for the behavioral deficit, RU486 treatment rescues this abnormal synaptic phenotype. These preclinical results define glucocorticoid signaling as a contributing factor to both episodic memory loss and early synaptic failure in this AD mouse model, and suggest that glucocorticoid receptor targeting strategies could be beneficial to delay AD onset.Neuropsychopharmacology accepted article preview online, 27 January 2015. doi:10.1038/npp.2015.25.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 01/2015; 40(7). DOI:10.1038/npp.2015.25 · 7.05 Impact Factor
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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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