title: Protein Phosphatase-1 Inhibitor-2 Is a Novel Memory Suppressor.
abstract: Reversible phosphorylation, a fundamental regulatory mechanism required for many biological processes including memory formation, is coordinated by the opposing actions of protein kinases and phosphatases. Type I protein phosphatase (PP1), in particular, has been shown to constrain learning and memory formation. However, how PP1 might be regulated in memory is still not clear. Our previous work has elucidated that PP1 inhibitor-2 (I-2) is an endogenous regulator of PP1 in hippocampal and cortical neurons (Hou et al., 2013). Contrary to expectation, our studies of contextual fear conditioning and novel object recognition in I-2 heterozygous mice suggest that I-2 is a memory suppressor. In addition, lentiviral knock-down of I-2 in the rat dorsal hippocampus facilitated memory for tasks dependent on the hippocampus. Our data indicate that I-2 suppresses memory formation, probably via negatively regulating the phosphorylation of cAMP/calcium response element-binding protein (CREB) at serine 133 and CREB-mediated gene expression in dorsal hippocampus. Surprisingly, the data from both biochemical and behavioral studies suggest that I-2, despite its assumed action as a PP1 inhibitor, is a positive regulator of PP1 function in memory formation.
  
  
  CONCLUSIONS
  We found that inhibitor-2 acts as a memory suppressor through its positive functional influence on type I protein phosphatase (PP1), likely resulting in negative regulation of cAMP/calcium response element-binding protein (CREB) and CREB-activated gene expression. Our studies thus provide an interesting example of a molecule with an in vivo function that is opposite to its in vitro function. PP1 plays critical roles in many essential physiological functions such as cell mitosis and glucose metabolism in addition to its known role in memory formation. PP1 pharmacological inhibitors would thus not be able to serve as good therapeutic reagents because of its many targets. However, identification of PP1 inhibitor-2 as a critical contributor to suppression of memory formation by PP1 may provide a novel therapeutic target for memory-related diseases.
authors.affiliation: Neuroscience Center of Excellence, School of Medicine, and.
authors.forename: Hongtian
authors.initials: H
authors.lastname: Yang
authors.affiliation: Neuroscience Center of Excellence, School of Medicine, and.
authors.forename: Hailong
authors.initials: H
authors.lastname: Hou
authors.affiliation: Neuroscience Program and.
authors.forename: Amanda
authors.initials: A
authors.lastname: Pahng
authors.affiliation: Neuroscience Center of Excellence, School of Medicine, and.
authors.forename: Hua
authors.initials: H
authors.lastname: Gu
authors.affiliation: Department of Psychiatry, Yale University, New Haven, Connecticut 06511.
authors.forename: Angus C
authors.initials: AC
authors.lastname: Nairn
authors.affiliation: Department of Cell Biology and Anatomy, Louisiana State University Health Science Center, New Orleans, Louisiana 70112.
authors.forename: Ya-Ping
authors.initials: YP
authors.lastname: Tang
authors.affiliation: Department of Psychology, Tulane University, New Orleans, Louisiana 70118, and.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Colombo
authors.affiliation: Neuroscience Center of Excellence, School of Medicine, and Department of Cell Biology and Anatomy, Louisiana State University Health Science Center, New Orleans, Louisiana 70112, hxia@lsuhsc.edu.
authors.forename: Houhui
authors.initials: H
authors.lastname: Xia
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005260:Female; D006624:Hippocampus / Q000502:physiology; D008297:Male; D018782:Maze Learning / Q000502:physiology; D008568:Memory / Q000502:physiology*; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D054645:Protein Phosphatase 1 / Q000037:antagonists & inhibitors* / Q000502:physiology*; D011506:Proteins / Q000502:physiology*; D051381:Rats; D000097847:Protein Phosphatase Inhibitory Proteins
chemical_list: D054645:Protein Phosphatase 1; D011506:Proteins; C024833:protein phosphatase inhibitor-2; D000097847:Protein Phosphatase Inhibitory Proteins
keywords: CREB; Protein phosphatase 1; RNAi; inhibitor 2; knock-out; memory