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The Journal of Neuroscience, January 2, 2008, 28(1):154-162; doi:10.1523/JNEUROSCI.4109-07.2008

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

Gaël F. Hédou,^1 * Kyoko Koshibu,^1 * Mélissa Farinelli,¹ Ertugrul Kilic,² Christine E. Gee,¹ Ulkan Kilic,² Karsten Baumgärtel,¹ Dirk M. Hermann,² and Isabelle M. Mansuy¹

¹Brain Research Institute, Medical Faculty, University of Zurich and Department of Biology, Swiss Federal Institute of Technology, CH-8057 Zurich, Switzerland, and ²Department of Neurology, University Hospital Zurich, CH-8091 Zurich, Switzerland

Correspondence should be addressed to Isabelle M. Mansuy, Brain Research Institute, Medical Faculty, University of Zurich and Department of Biology, Swiss Federal Institute of Technology, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland. Email: mansuy{at}hifo.unizh.ch

Protein kinases and phosphatases can alter the impact of excitotoxicity resulting from ischemia by concurrently modulating apoptotic/survival pathways. Here, we show that protein phosphatase 1 (PP1), known to constrain neuronal signaling and synaptic strength (Mansuy et al., 1998; Morishita et al., 2001), critically regulates neuroprotective pathways in the adult brain. When PP1 is inhibited pharmacologically or genetically, recovery from oxygen/glucose deprivation (OGD) in vitro, or ischemia in vivo is impaired. Furthermore, in vitro, inducing LTP shortly before OGD similarly impairs recovery, an effect that correlates with strong PP1 inhibition. Conversely, inducing LTD before OGD elicits full recovery by preserving PP1 activity, an effect that is abolished by PP1 inhibition. The mechanisms of action of PP1 appear to be coupled with several components of apoptotic pathways, in particular ERK1/2 (extracellular signal-regulated kinase 1/2) whose activation is increased by PP1 inhibition both in vitro and in vivo. Together, these results reveal that the mechanisms of recovery in the adult brain critically involve PP1, and highlight a novel physiological function for long-term potentiation and long-term depression in the control of brain damage and repair.

Key words: PP1; ischemia; OGD; cell death; plasticity; hippocampus

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Received Sept. 11, 2007; revised Nov. 10, 2007; accepted Nov. 10, 2007.

Correspondence should be addressed to Isabelle M. Mansuy, Brain Research Institute, Medical Faculty, University of Zurich and Department of Biology, Swiss Federal Institute of Technology, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland. Email: mansuy{at}hifo.unizh.ch

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