Long-term memories are believed to be due to persistent changes in synaptic strength. Although the molecular mechanisms initiating these changes have been extensively studied, the mechanisms maintaining these changes, which may contribute to storing long-term memory, have been unknown. Recently, however, a candidate molecular mechanism has emerged for maintaining a persistent form of synaptic enhancement triggered by strong afferent stimulation of synapses, known as long-term potentiation (LTP). The key molecule in this maintenance mechanism is a brain-specific, protein kinase C isoform, PKM6. Unlike other PKC isoforms that require second messengers for activation, PKM6 consists of an independent PKC catalytic domain that is constitutively active. PKM6 is produced from a PKM6 mRNA, and the amount of the kinase increases with LTP induction. The persistent activity of the kinase is then both necessary and sufficient for maintaining the synaptic enhancement. Postsynaptic perfusion of PKM6 enhances synaptic transmission, and inhibition of PKM6 activity reverses previously established LTP. Recently, PKM6 inhibition has been found to disrupt the storage of previously established long-term memories. These data indicate that PKM6 is a candidate molecule uniquely important for information storage at synapses and during behavior. Thus the overall goal of this application is to elucidate in mechanistic detail the function of PKM6 in persistent synaptic enhancement and memory storage. Our 3 Specific Aims are: 1) To characterize the mechanisms by which PKM6 enhances synaptic strength. We found that PKM6 potentiates synaptic strength by increasing the number of postsynaptic AMPA receptors (AMPARs) through interactions between the AMPAR GluR2 subunit and the trafficking protein NSF. We will examine whether this potentiation is through increased exocytosis and/or decreased endocytosis of postsynaptic AMPARs and the function of this altered trafficking in memory maintained by PKM6. 2) To determine whether preexisting and newly translated PKM6 mediate distinct phases of potentiation during LTP. Preliminary evidence indicates that antisense oligodeoxynucleotides blocking new PKM6 synthesis prevents the persistence of a phase of LTP. We will determine whether this new synthesis occurs at dendritic sites. 3) To determine the role of preexisting, newly translated, and new gene transcription of PKM6 in distinct phase of memory. PKM6 maintains memory up to several months after training. We will employ both antisense to block translation of PKM6 mRNA and conditional genetic deletion of PKM6 to examine the function of distinct mechanisms of expression of PKM6 in different phases of memory. These 3 aims will provide fundamental new information on a potential molecular mechanism for maintaining synaptic and behavioral information storage, which may be relevant to both normal memory and its disorders.

Public Health Relevance

How long-term memories are stored in the brain is a fundamental neurobiological question, with many implications for neurology and psychiatry, but the molecular mechanisms of memory maintenance have been unknown. Recently, however, the persistent action of a protein kinase, termed PKMzeta, has been found to be one potential mechanism for maintaining memory. This application is to characterize the functional mechanisms by which PKMzeta maintains long-term information at synapses and during behavioral memory storage.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Method to Extend Research in Time (MERIT) Award (R37)
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Neurobiology of Learning and Memory Study Section (LAM)
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Asanuma, Chiiko
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Suny Downstate Medical Center
Schools of Medicine
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Sacktor, Todd Charlton; Fenton, André Antonio (2018) What does LTP tell us about the roles of CaMKII and PKM? in memory? Mol Brain 11:77
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Gao, Peng Penny; Goodman, Jeffrey H; Sacktor, Todd Charlton et al. (2018) Persistent Increases of PKM? in Sensorimotor Cortex Maintain Procedural Long-Term Memory Storage. iScience 5:90-98
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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:
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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

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