Long-term modifications in synaptic strength are thought to provide the physiological basis of learning and memory. These changes in synaptic strength are maintained initially by persistently active protein kinases. In the long term, these changes are maintained by the synthesis of new proteins. The Principal Investigator has identified a persistently active form of protein kinase C (PKMz) that is newly synthesized in hippocampal area CA1 during long-term potentiation. Levels of PKMz, the persistently active independent catalytic domain of the PKCz isoform, increase in LTP whereas stimuli that lead to long-term depression (LTD) result in decreases in the level of PKMz. The goal of this competing continuation is to characterize the mechanisms that mediate the increase in PKMz observed following LTP and LTD inducing stimuli. Recent evidence suggests that PKMz is produced by a brain specific mRNA that encodes only the catalytic domain of PKCz and thus increases in PKMz may result from either the increased translation of this mRNA or increased transcription of this mRNA from DNA. The first specific aim will determine the role of increased translation by examining the local synthesis of PKMz and the effects of agents that inhibit the upregulation of translation. The second specific aim will examine the activity dependent regulation of PKMz mRNA during LTP and LTD. In the third specific aim, the effect of increased PKMz on synaptic transmission will be determined by perfusing PKMz into neurons and by transgenic overexpressing. These three specific aims will generate fundamental information about the role of PKMz in protein synthesis dependent forms of synaptic plasticity and may provide concrete molecular mechanisms responsible for the persistence of memory.
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| 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: |
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| 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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