Inducible and Reversible Enhancement of Learning, Memory, and Long-Term Potentiation by Genetic Inhibition of Calcineurin
Open accessAbstract
The threshold for hippocampal-dependent synaptic plasticity and memory storage is thought to be determined by the balance between protein phosphorylation and dephosphorylation mediated by the kinase PKA and the phosphatase calcineurin. To establish whether endogenous calcineurin acts as an inhibitory constraint in this balance, we examined the effect of genetically inhibiting calcineurin on plasticity and memory. Using the doxycycline-dependent rtTA system to express a calcineurin inhibitor reversibly in the mouse brain, we find that the transient reduction of calcineurin activity facilitates LTP in vitro and in vivo. This facilitation is PKA dependent and persists over several days in vivo. It is accompanied by enhanced learning and strengthened short- and long-term memory in several hippocampal-dependent spatial and nonspatial tasks. The LTP and memory improvements are reversed fully by suppression of transgene expression. These results demonstrate that endogenous calcineurin constrains LTP and memory.
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The findings of impaired LTD and enhanced LTP with AKAP-CaN anchoring disruption are similar to previous studies using less-specific genetic or pharmacologic inhibition of CaN activity in hippocampal slices.
“Our findings of impaired LTD and enhanced LTP with AKAP-CaN anchoring disruption are similar to previous studies using less-specific genetic or pharmacologic inhibition of CaN activity in hippocampal slices”
From AKAP150-Anchored Calcineurin Regulates Synaptic Plasticity by Limiting Synaptic Incorporation of Ca<sup>2+</sup>-Permeable AMPA Receptors (2012) · cites this paper as Malleret et al., 2001
The results for ΔPIX mice are similar to those in slices from older mice using a genetically-encoded inhibitor to partially block CaN activity.
“However, our results for ΔPIX mice are similar to those in slices from older mice using a genetically-encoded inhibitor to partially block CaN activity”
From AKAP150-Anchored Calcineurin Regulates Synaptic Plasticity by Limiting Synaptic Incorporation of Ca<sup>2+</sup>-Permeable AMPA Receptors (2012) · cites this paper as Malleret et al., 2001
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“However, LTP is normal in conditional CaN knockout animals when induced by standard 1 100 Hz, 1 s HFS but is slightly enhanced when using weaker 40 Hz stimulation (Zeng et al., 2001).”
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- Authors
- Malleret, G., Haditsch, U., Genoux, D., Jones, M. W., Bliss, T. V. P., Vanhoose, A. M., Weitlauf, C., Kandel, E. R., Winder, D. G., & Mansuy, I. M.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- ETH Zurich (CH)
- National Institute for Medical Research (GB)
- Vanderbilt University (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Mansuy, Isabelle M.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2001-03
- Volume
- 104
- Issue
- 5
- Pages
- 675-686
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W2093906292
- Cited by
- 470
- References
- 3
- Citations by year
- 2026: 6 · 2025: 4 · 2024: 5 · 2023: 2 · 2022: 7 · 2021: 9 · 2020: 6 · 2019: 11 · 2018: 9 · 2017: 13 · 2016: 14 · 2015: 15 · 2014: 11 · 2013: 22 · 2012: 19
- FWCI
- 24.49
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Explore Bristol Research (submittedVersion)
- Bristol Research (University of Bristol) (submittedVersion)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Keywords
- calcineurin, long-term potentiation, hippocampal-dependent memory, learning, protein phosphorylation, protein dephosphorylation, protein kinase A, synaptic plasticity, doxycycline-inducible expression, spatial memory
- MeSH terms
- Animals, Anti-Bacterial Agents, Conditioning, Psychological, Doxycycline, Electric Stimulation, Form Perception, Gene Expression Regulation, Memory, Short-Term, Mice, Inbred C57BL, Mice, Transgenic, Neuronal Plasticity, Signal Transduction, Long-Term Potentiation, Dentate Gyrus, Transgenes, Calcineurin, Mice, Calcineurin Inhibitors, In Vitro Techniques
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