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
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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Article: 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
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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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- "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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- "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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