Protein phosphatase 1-dependent bidirectional synaptic plasticity controls ischemic recovery in the adult brain.
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.
Hédou
Gaël F
GF
Brain Research Institute, Medical Faculty, University of Zurich and Department of Biology, Swiss Federal Institute of Technology, CH-8057 Zurich, Switzerland.
Koshibu
Kyoko
K
Farinelli
Mélissa
M
Kilic
Ertugrul
E
Gee
Christine E
CE
Kilic
Ulkan
U
Baumgärtel
Karsten
K
Hermann
Dirk M
DM
Mansuy
Isabelle M
IM
D000818:Animals; D030801:Animals, Genetically Modified; D002545:Brain Ischemia / Q000473:pathology* / Q000503:physiopathology*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D004318:Doxycycline / Q000008:administration & dosage; D004558:Electric Stimulation / Q000379:methods; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D005947:Glucose / Q000172:deficiency; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology / Q000528:radiation effects; D000860:Hypoxia / Q000150:complications; D066298:In Vitro Techniques; D036881:Long-Term Synaptic Depression / Q000502:physiology / Q000528:radiation effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009473:Neuronal Plasticity / Q000502:physiology*; D054645:Protein Phosphatase 1 / Q000502:physiology*; D011506:Proteins / Q000235:genetics; D011714:Pyrans / Q000494:pharmacology; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D013141:Spiro Compounds / Q000494:pharmacology
D004791:Enzyme Inhibitors; D011506:Proteins; D011714:Pyrans; D013141:Spiro Compounds; C073882:phosphoprotein phosphatase inhibitor 1; C053079:tautomycin; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D054645:Protein Phosphatase 1; D005947:Glucose; D004318:Doxycycline