Long-term changes in synaptic strength are thought to contribute to the cellular basis of memory. These changes can be divided into two phases: a brief induction, triggering the modification, and a persistent maintenance, sustaining it over time. We have found a new form of atypical PKC, called PKMzeta, increases during the maintenance of long-term potentiation (LTP), a widely studied, putative cellular model of memory. PKC is usually held in an inactive state because its regulatory domain inhibits its catalytic domain; second messengers activate the enzyme by transiently releasing this autoinhibition. In contrast, PKMzeta is an independent PKC catalytic domain and, lacking the inhibition from a regulatory domain, is autonomously active. We found that increased function of PKMzeta is sufficient to enhance synaptic transmission when the kinase is introduced into CA1 pyramidal cells. The persistently increased activity of PKMzeta is also necessary for maintenance, because specific inhibitors of PKMzeta reverse established LTP. Our overall goal then is to elucidate the physiological mechanisms that increase PKMzeta function in LTP maintenance. The 1st aim is to examine posttranslational mechanisms for increasing PKMzeta function. Preliminary data suggest that PKMzeta is phosphorylated through the PI3-kinase/PDKl pathway. Using phosphorylation state-specific antisera to PKMzeta, we will test the hypotheses that this modification increases PKMzeta's function in LTP and dephosphorylation of this site decreases its activity in LTD. The 2nd aim is to determine the translational mechanisms for increasing PKMzeta function. PKM, the independent catalytic domain of PKC, is usually thought of as a proteolytic fragment of PKC. Our preliminary data, however, show that brain PKMzeta, is formed physiologically, not by proteolysis, but by translation of a brain-specific PKMzeta mRNA. This PKMzeta, mRNA is targeted to dendrites, and we will examine the regulation of increased local translation by the MAP-kinase and rapamycin-sensitive pathways. The 3rd aim examines the transcriptional mechanisms for increasing PKMzeta function. New data indicate that increased PKMzeta function is critical for late LTP. We find that an internal promoter within the PKCS, gene transcribes the PKMzeta mRNA. A long 5'untranslated region (5'UTR) on some PKMzeta mRNAs inhibits its translation. Regulation of the PKMzeta transcription start site during LTP may produce PKMC, mRNAs with shorter 5'UTRs, thus increasing the message's translational capacity and providing a long-term mechanism for maintaining increased PKMzeta function. These 3 goals aim to understand in mechanistic detail the physiological increase of PKMzeta function in LTP maintenance, which might help provide a unifying framework for the complex signaling pathways of memory.
| Hsieh, Changchi; Tsokas, Panayiotis; Serrano, Peter et al. (2017) Persistent increased PKM? in long-term and remote spatial memory. Neurobiol Learn Mem 138:135-144 |
| Lesburguères, Edith; Tsokas, Panayiotis; Sacktor, Todd Charlton et al. (2017) The Object Context-place-location Paradigm for Testing Spatial Memory in Mice. Bio Protoc 7: |
| Tsokas, Panayiotis; Hsieh, Changchi; Yao, Yudong et al. (2016) Compensation for PKM? in long-term potentiation and spatial long-term memory in mutant mice. Elife 5: |
| Ko, Hyoung-Gon; Kim, Ji-Il; Sim, Su-Eon et al. (2016) The role of nuclear PKM? in memory maintenance. Neurobiol Learn Mem 135:50-56 |
| Jalil, Sajiya J; Sacktor, Todd Charlton; Shouval, Harel Z (2015) Atypical PKCs in memory maintenance: the roles of feedback and redundancy. Learn Mem 22:344-53 |
| Dong, Zhifang; Han, Huili; Li, Hongjie et al. (2015) Long-term potentiation decay and memory loss are mediated by AMPAR endocytosis. J Clin Invest 125:234-47 |
| Hernández, A Iván; Oxberry, William C; Crary, John F et al. (2014) Cellular and subcellular localization of PKM?. Philos Trans R Soc Lond B Biol Sci 369:20130140 |
| Eom, Taesun; Muslimov, Ilham A; Tsokas, Panayiotis et al. (2014) Neuronal BC RNAs cooperate with eIF4B to mediate activity-dependent translational control. J Cell Biol 207:237-52 |
| Yao, Yudong; Shao, Charles; Jothianandan, Desingarao et al. (2013) Matching biochemical and functional efficacies confirm ZIP as a potent competitive inhibitor of PKM? in neurons. Neuropharmacology 64:37-44 |
| Vélez-Hernández, María E; Vázquez-Torres, Rafael; Velasquez-Martinez, Maria C et al. (2013) Inhibition of Protein kinase Mzeta (PKM?) in the mesolimbic system alters cocaine sensitization in rats. J Drug Alcohol Res 2:235669 |
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