Protein Phosphatase-1 Inhibitor-2 Is a Novel Memory Suppressor

Abstract

Reversiblephosphorylation,afundamentalregulatorymechanismrequiredformanybiologicalprocessesincludingmemoryformation,iscoordinated bytheopposingactionsofproteinkinasesandphosphatases.TypeIproteinphosphatase(PP1),inparticular,hasbeenshowntoconstrainlearningand 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 endogenousregulatorofPP1inhippocampalandcorticalneurons(Houetal.,2013).Contrarytoexpectation,ourstudiesofcontextualfearconditioning andnovelobjectrecognitioninI-2heterozygousmicesuggestthatI-2isamemorysuppressor.Inaddition,lentiviralknock-downofI-2intheratdorsal 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.

Inhibitor-2In VivoEnhances Protein Phosphatase-1 Activity and Suppresses Learning and Memory: Possible Implication for the Progression of Tau Pathology

“…In line with this, Yang et al (2015) found that phosphorylated CREB levels and CREB-mediated gene expression were increased after I-2 reduction in both rats and mice (Yang et al, 2015, their Fig. 3).…”

“…Heterozygous animals (I-2 ϩ/Ϫ ) on the other hand, were healthy and showed no abnormal phenotypes. I-2 levels in the brains of these animals were ϳ50% of those detected in wild-type littermates (Yang et al, 2015).…”

“…ϩ/Ϫ mice showed enhanced performance compared with wild types in both novel object recognition and contextual fear conditioning tasks, suggesting that in vivo, I-2 limits memory and learning (Yang et al, 2015, their Fig. 1 D, E).…”

“…However, results by Hou et al (2013) suggested that the in vivo function of I-2 might be more complex than merely inhibiting PP1 activity, because I-2 knock-down led to decreased, rather than increased, PP1 activity in rat primary cortical neurons. A follow-up study by the same group revealed that in vivo I-2 indeed enhances rather than suppresses PP1 activity (Yang et al, 2015). Yang et al (2015) examined the effects of heterozygous I-2 knock-out in mice and shRNA-mediated knockdown of I-2 in rats.…”

“…A follow-up study by the same group revealed that in vivo I-2 indeed enhances rather than suppresses PP1 activity (Yang et al, 2015). Yang et al (2015) examined the effects of heterozygous I-2 knock-out in mice and shRNA-mediated knockdown of I-2 in rats. In homozygous I-2 knock-out mice, I-2 was completely absent and these animals died as embryos.…”