What does LTP tell us about the roles of CaMKII and PKMζ in memory?
Abstract In “Criteria for identifying the molecular basis of the engram (CaMKII, PKMζ),” Lisman proposes that elucidating the mechanism of LTP maintenance is key to understanding memory storage. He suggests three criteria for a maintenance mechanism to evaluate data on CaMKII and PKMζ as memory stor...
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| Format: | Article |
| Language: | English |
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BMC
2018-12-01
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| Series: | Molecular Brain |
| Online Access: | http://link.springer.com/article/10.1186/s13041-018-0420-5 |
| _version_ | 1819128210555666432 |
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| author | Todd Charlton Sacktor André Antonio Fenton |
| author_facet | Todd Charlton Sacktor André Antonio Fenton |
| author_sort | Todd Charlton Sacktor |
| collection | DOAJ |
| description | Abstract In “Criteria for identifying the molecular basis of the engram (CaMKII, PKMζ),” Lisman proposes that elucidating the mechanism of LTP maintenance is key to understanding memory storage. He suggests three criteria for a maintenance mechanism to evaluate data on CaMKII and PKMζ as memory storage molecules: necessity, occlusion, and erasure. Here we show that when the criteria are tested, the results reveal important differences between the molecules. Inhibiting PKMζ reverses established, protein synthesis-dependent late-LTP, without affecting early-LTP or baseline synaptic transmission. In contrast, blocking CaMKII has two effects: 1) inhibiting CaMKII activity blocks LTP induction but not maintenance, and 2) disrupting CaMKII interactions with NMDARs in the postsynaptic density (PSD) depresses both early-LTP and basal synaptic transmission equivalently. To identify a maintenance mechanism, we propose a fourth criterion — persistence. PKMζ increases for hours during LTP maintenance in hippocampal slices, and for over a month in specific brain regions during long-term memory storage in conditioned animals. In contrast, increased CaMKII activity lasts only minutes following LTP induction, and CaMKII translocation to the PSD in late-LTP or memory has not been reported. Lastly, do the PKMζ and CaMKII models integrate the many other signaling molecules important for LTP? Activity-dependent PKMζ synthesis is regulated by many of the signaling molecules that induce LTP, including CaMKII, providing a plausible mechanism for new gene expression in the persistent phosphorylation by PKMζ maintaining late-LTP and memory. In contrast, CaMKII autophosphorylation and translocation do not appear to require new protein synthesis. Therefore, the cumulative evidence supports a core role for PKMζ in late-LTP and long-term memory maintenance, and separate roles for CaMKII in LTP induction and for the maintenance of postsynaptic structure and synaptic transmission in a mechanism distinct from late-LTP. |
| first_indexed | 2024-12-22T08:24:12Z |
| format | Article |
| id | doaj.art-8c1e3e0ed80046b88ec17fb55feff8f9 |
| institution | Directory Open Access Journal |
| issn | 1756-6606 |
| language | English |
| last_indexed | 2024-12-22T08:24:12Z |
| publishDate | 2018-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Brain |
| spelling | doaj.art-8c1e3e0ed80046b88ec17fb55feff8f92022-12-21T18:32:40ZengBMCMolecular Brain1756-66062018-12-011111910.1186/s13041-018-0420-5What does LTP tell us about the roles of CaMKII and PKMζ in memory?Todd Charlton Sacktor0André Antonio Fenton1Department of Physiology and Pharmacology, The Robert F. Furchgott Center for Neural and Behavioral Science, State University of New York Downstate Medical CenterDepartment of Physiology and Pharmacology, The Robert F. Furchgott Center for Neural and Behavioral Science, State University of New York Downstate Medical CenterAbstract In “Criteria for identifying the molecular basis of the engram (CaMKII, PKMζ),” Lisman proposes that elucidating the mechanism of LTP maintenance is key to understanding memory storage. He suggests three criteria for a maintenance mechanism to evaluate data on CaMKII and PKMζ as memory storage molecules: necessity, occlusion, and erasure. Here we show that when the criteria are tested, the results reveal important differences between the molecules. Inhibiting PKMζ reverses established, protein synthesis-dependent late-LTP, without affecting early-LTP or baseline synaptic transmission. In contrast, blocking CaMKII has two effects: 1) inhibiting CaMKII activity blocks LTP induction but not maintenance, and 2) disrupting CaMKII interactions with NMDARs in the postsynaptic density (PSD) depresses both early-LTP and basal synaptic transmission equivalently. To identify a maintenance mechanism, we propose a fourth criterion — persistence. PKMζ increases for hours during LTP maintenance in hippocampal slices, and for over a month in specific brain regions during long-term memory storage in conditioned animals. In contrast, increased CaMKII activity lasts only minutes following LTP induction, and CaMKII translocation to the PSD in late-LTP or memory has not been reported. Lastly, do the PKMζ and CaMKII models integrate the many other signaling molecules important for LTP? Activity-dependent PKMζ synthesis is regulated by many of the signaling molecules that induce LTP, including CaMKII, providing a plausible mechanism for new gene expression in the persistent phosphorylation by PKMζ maintaining late-LTP and memory. In contrast, CaMKII autophosphorylation and translocation do not appear to require new protein synthesis. Therefore, the cumulative evidence supports a core role for PKMζ in late-LTP and long-term memory maintenance, and separate roles for CaMKII in LTP induction and for the maintenance of postsynaptic structure and synaptic transmission in a mechanism distinct from late-LTP.http://link.springer.com/article/10.1186/s13041-018-0420-5 |
| spellingShingle | Todd Charlton Sacktor André Antonio Fenton What does LTP tell us about the roles of CaMKII and PKMζ in memory? Molecular Brain |
| title | What does LTP tell us about the roles of CaMKII and PKMζ in memory? |
| title_full | What does LTP tell us about the roles of CaMKII and PKMζ in memory? |
| title_fullStr | What does LTP tell us about the roles of CaMKII and PKMζ in memory? |
| title_full_unstemmed | What does LTP tell us about the roles of CaMKII and PKMζ in memory? |
| title_short | What does LTP tell us about the roles of CaMKII and PKMζ in memory? |
| title_sort | what does ltp tell us about the roles of camkii and pkmζ in memory |
| url | http://link.springer.com/article/10.1186/s13041-018-0420-5 |
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