Protein phosphatase 1-dependent bidirectional synaptic plasticity controls ischemic recovery in the adult brain

TY - JOUR

T1 - Protein phosphatase 1-dependent bidirectional synaptic plasticity controls ischemic recovery in the adult brain

AU - Hédou, Gaël F

AU - Koshibu, Kyoko

AU - Farinelli, Mélissa

AU - Kilic, Ertugrul

AU - Gee, Christine E

AU - Kilic, Ulkan

AU - Baumgärtel, Karsten

AU - Hermann, Dirk M

AU - Mansuy, Isabelle M

PY - 2008/1/2

Y1 - 2008/1/2

N2 - 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.

AB - 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.

KW - Animals

KW - Animals, Genetically Modified

KW - Anoxia

KW - Brain Ischemia

KW - Calcium-Calmodulin-Dependent Protein Kinase Type 2

KW - Disease Models, Animal

KW - Dose-Response Relationship, Drug

KW - Dose-Response Relationship, Radiation

KW - Doxycycline

KW - Electric Stimulation

KW - Enzyme Inhibitors

KW - Gene Expression Regulation

KW - Glucose

KW - Hippocampus

KW - In Vitro Techniques

KW - Long-Term Synaptic Depression

KW - Mice

KW - Mice, Inbred C57BL

KW - Neuronal Plasticity

KW - Protein Phosphatase 1

KW - Proteins

KW - Pyrans

KW - Recovery of Function

KW - Spiro Compounds

U2 - 10.1523/JNEUROSCI.4109-07.2008

DO - 10.1523/JNEUROSCI.4109-07.2008

M3 - SCORING: Journal article

C2 - 18171933

VL - 28

SP - 154

EP - 162

JO - J NEUROSCI

JF - J NEUROSCI

SN - 0270-6474

IS - 1

ER -