CoChat
Sign Up
Cited by 498Memory and Neural MechanismsNeuroscience and Neuropharmacology ResearchSignaling Pathways in Disease

Forebrain-Specific Calcineurin Knockout Selectively Impairs Bidirectional Synaptic Plasticity and Working/Episodic-like Memory

Open access
Zeng, Hongkui, Chattarji, Sumantra, Barbarosie, Michaela, Rondi-Reig, Laure, Philpot, Benjamin D., Miyakawa, Tsuyoshi, Bear, Mark F., Tonegawa, Susumu·2001·Cell
DOI 10.1016/s0092-8674(01)00585-2
Open this paper in CoChat — free accountOpen PDF

Abstract

Calcineurin is a calcium-dependent protein phosphatase that has been implicated in various aspects of synaptic plasticity. By using conditional gene-targeting techniques, we created mice in which calcineurin activity is disrupted specifically in the adult forebrain. At hippocampal Schaffer collateral-CA1 synapses, LTD was significantly diminished, and there was a significant shift in the LTD/LTP modification threshold in mutant mice. Strikingly, although performance was normal in hippocampus-dependent reference memory tasks, including contextual fear conditioning and the Morris water maze, the mutant mice were impaired in hippocampus-dependent working and episodic-like memory tasks, including the delayed matching-to-place task and the radial maze task. Our results define a critical role for calcineurin in bidirectional synaptic plasticity and suggest a novel mechanistic distinction between working/episodic-like memory and reference memory.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1016/s0092-8674(01)00585-2

Cites

4 of 4 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • The study did not see enhanced induction or expression of LTP in ΔPIX mice using weaker stimuli of 50 Hz or 10 Hz that enhance potentiation in conditional CaN knockout mice and GluA1 S831,845D mice.

    “We did not see enhanced induction or expression of LTP in ΔPIX mice using weaker stimuli of 50 Hz or 10 Hz that enhance potentiation in conditional CaN knockout mice (Zeng et al., 2001) and GluA1 S831,845D mice that mimic constitutive GluA1 phosphorylation”

    From AKAP150-Anchored Calcineurin Regulates Synaptic Plasticity by Limiting Synaptic Incorporation of Ca<sup>2+</sup>-Permeable AMPA Receptors (2012) · cites this paper as Zeng et al., 2001

    The passage headed “Impaired LTD But Normal LTP and Depotentiation at the Schaffer Collateral-CA1 Synapse” reports slight potentiation at 10 Hz and greater LTP at 40 Hz in conditional calcineurin knockout mice than in controls. It does not report a 50 Hz test, so the cited paper supports the comparison at 10 Hz but not the specified 50 Hz frequency. The statement about ΔPIX mice is the citing authors’ own result, not a finding attributed to this source. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Forebrain-specific CaN knockout mice, like ΔPIX mice, exhibit a lack of LTD but maintain normal depotentiation.

    “In addition, forebrain-specific CaN knockout mice, like our ΔPIX mice, exhibit a lack of LTD but maintain normal depotentiation”

    From AKAP150-Anchored Calcineurin Regulates Synaptic Plasticity by Limiting Synaptic Incorporation of Ca<sup>2+</sup>-Permeable AMPA Receptors (2012) · cites this paper as Zeng et al., 2001

    The Introduction and the passage headed “Impaired LTD But Normal LTP and Depotentiation at the Schaffer Collateral-CA1 Synapse” report diminished, not absent, LTD in the knockout mice. The depotentiation passage reports comparable responses in mutant and control slices. No page numbers are available in our copy. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • 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 Zeng et al., 2001

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 27

  1. [1]1. Bear, M.F. ∙ Abraham, W.C. Long-term depression in hippocampus Annu. Rev. Neurosci. 1996; 19:437-462 Crossref Scopus (507) PubMed Google Scholar
  2. [3]3. Becker, J.T. ∙ Walker, J.A. ∙ Olton, D.S. Neuroanatomical bases of spatial memory Brain Res. 1980; 200:307-320 Crossref Scopus (243) PubMed Google Scholar
  3. [4]4. Bito, H. ∙ Deisseroth, K. ∙ Tsien, R.W. CREB phosphorylation and dephosphorylationa Ca(2+)- and stimulus duration-dependent switch for hippocampal gene expression Cell. 1996; 87:1203-1214 Full Text Full Text (PDF) Scopus (999) PubMed Google Scholar
  4. [5]5. Bunsey, M. ∙ Eichenbaum, H. Conservation of hippocampal memory function in rats and humans Nature. 1996; 379:255-257 Crossref Scopus (530) PubMed Google Scholar
  5. [6]6. Chen, G. ∙ Chen, K.S. ∙ Knox, J. ... A learning deficit related to age and beta-amyloid plaques in a mouse model of Alzheimer's disease Nature. 2000; 408:975-979 Crossref Scopus (9) PubMed Google Scholar
  6. [7]7. Coghlan, V.M. ∙ Perrino, B.A. ∙ Howard, M. ... Association of protein kinase A and protein phosphatase 2B with a common anchoring protein Science. 1995; 267:108-111 Crossref Scopus (533) PubMed Google Scholar
  7. [8]8. Colledge, M. ∙ Dean, R.A. ∙ Scott, G.K. ... Targeting of PKA to glutamate receptors through a MAGUK-AKAP complex Neuron. 2000; 27:107-119 Full Text Full Text (PDF) Scopus (425) PubMed Google Scholar
  8. [9]9. Gerlai, R. Gene-targeting studies of mammalian behavioris it the mutation or the background genotype? Trends Neurosci. 1996; 19:177-181 Full Text Full Text (PDF) Scopus (810) PubMed Google Scholar
  9. [10]10. Goldman-Rakic, P.S. Regional and cellular fractionation of working memory Proc. Natl. Acad. Sci. USA. 1996; 93:13473-13480 Crossref Scopus (697) PubMed Google Scholar
  10. [12]12. Jones, M.V. ∙ Westbrook, G.L. Shaping of IPSCs by endogenous calcineurin activity J. Neurosci. 1997; 17:7626-7633 Crossref PubMed Google Scholar
  11. [13]13. Kirkwood, A. ∙ Bear, M.F. Homosynaptic long-term depression in the visual cortex J. Neurosci. 1994; 14:3404-3412 Crossref PubMed Google Scholar
  12. [14]14. Klee, C.B. ∙ Ren, H. ∙ Wang, X. Regulation of the calmodulin-stimulated protein phosphatase, calcineurin J. Biol. Chem. 1998; 273:13367-13370 Crossref Scopus (809) PubMed Google Scholar
  13. [15]15. Kontgen, F. ∙ Suss, G. ∙ Stewart, C. ... Targeted disruption of the MHC class II Aa gene in C57BL/6 mice Int. Immunol. 1993; 5:957-964 Crossref Scopus (313) PubMed Google Scholar
  14. [16]16. Kuno, T. ∙ Mukai, H. ∙ Ito, A. ... Distinct cellular expression of calcineurin Aα and Aβ in rat brain J. Neurochem. 1992; 58:1643-1651 Crossref Scopus (131) PubMed Google Scholar
  15. [17]17. Lai, M.M. ∙ Hong, J.J. ∙ Ruggiero, A.M. ... The calcineurin-dynamin 1 complex as a calcium sensor for synaptic vesicle endocytosis J. Biol. Chem. 1999; 274:25963-25966 Crossref Scopus (131) PubMed Google Scholar
  16. [18]18. Lee, H.K. ∙ Barbarosie, M. ∙ Kameyama, K. ... Regulation of distinct AMPA receptor phosphorylation sites during bidirectional synaptic plasticity Nature. 2000; 405:955-959 Crossref Scopus (925) PubMed Google Scholar
  17. [19]19. Lieberman, D.N. ∙ Mody, I. Regulation of NMDA channel function by endogenous Ca(2+)-dependent phosphatase Nature. 1994; 369:235-239 Crossref Scopus (446) PubMed Google Scholar
  18. [20]20. Lin, J.W. ∙ Ju, W. ∙ Foster, K. ... Distinct molecular mechanisms and divergent endocytotic pathways of AMPA receptor internalization Nat. Neurosci. 2000; 3:1282-1290 Crossref Scopus (417) PubMed Google Scholar
  19. [21]21. Lisman, J. A mechanism for the Hebb and the anti-Hebb processes underlying learning and memory Proc. Natl. Acad. Sci. USA. 1989; 86:9574-9578 Crossref Scopus (897) PubMed Google Scholar
  20. [22]22. Liu, J.P. ∙ Sim, A.T. ∙ Robinson, P.J. Calcineurin inhibition of dynamin I GTPase activity coupled to nerve terminal depolarization Science. 1994; 265:970-973 Crossref Scopus (186) PubMed Google Scholar
  21. [23]23. Lu, Y.M. ∙ Mansuy, I.M. ∙ Kandel, E.R. ... Calcineurin-mediated LTD of GABAergic inhibition underlies the increased excitability of CA1 neurons associated with LTP Neuron. 2000; 26:197-205 Full Text Full Text (PDF) Scopus (247) PubMed Google Scholar
  22. [24]24. Malleret, G. ∙ Haditsch, U. ∙ Genoux, D. ... Inducible and reversible enhancement of learning, memory, and long-term potentiation by genetic inhibition of calcineurin Cell. 2001; 104:675-686 Full Text Full Text (PDF) Scopus (416) PubMed Google Scholar
  23. [25]25. Mansuy, I.M. ∙ Mayford, M. ∙ Jacob, B. ... Restricted and regulated overexpression reveals calcineurin as a key component in the transition from short-term to long-term memory Cell. 1998; 92:39-49 Full Text Full Text (PDF) Scopus (325) PubMed Google Scholar
  24. [26]26. Mansuy, I.M. ∙ Winder, D.G. ∙ Moallem, T.M. ... Inducible and reversible gene expression with the rtTA system for the study of memory Neuron. 1998; 21:257-265 Full Text Full Text (PDF) Scopus (214) PubMed Google Scholar
  25. [27]27. Marks, B. ∙ McMahon, H.T. Calcium triggers calcineurin-dependent synaptic vesicle recycling in mammalian nerve terminals Curr. Biol. 1998; 8:740-749 Full Text Full Text (PDF) Scopus (236) PubMed Google Scholar
  26. [28]28. Martin, S.J. ∙ Grimwood, P.D. ∙ Morris, R.G. Synaptic plasticity and memoryan evaluation of the hypothesis Annu. Rev. Neurosci. 2000; 23:649-711 Crossref Scopus (2248) PubMed Google Scholar
  27. [29]29. Merat, D.L. ∙ Hu, Z.Y. ∙ Carter, T.E. ... Bovine brain calmodulin-dependent protein phosphatase, regulation of subunit A activity by calmodulin and subunit B J. Biol. Chem. 1985; 260:11053-11059

Cited by

Sorted by citations

Authors
Zeng, H., Chattarji, S., Barbarosie, M., Rondi-Reig, L., Philpot, B. D., Miyakawa, T., Bear, M. F., & Tonegawa, S.
Affiliations
  • Howard Hughes Medical Institute (US)
  • Tata Institute of Fundamental Research (IN)
Corresponding author
Tonegawa, Susumu
ORCID
Venue
Cell
Publisher
Elsevier BV
Published
2001-11
Volume
107
Issue
5
Pages
617-629
ISSN
0092-8674 (ISSN-L)
DOI
10.1016/s0092-8674(01)00585-2
OpenAlex
W2102256305
Cited by
498
References
4
Citations by year
2026: 5 · 2025: 8 · 2024: 9 · 2023: 11 · 2022: 14 · 2021: 15 · 2020: 12 · 2019: 16 · 2018: 23 · 2017: 28 · 2016: 24 · 2015: 23 · 2014: 17 · 2013: 21 · 2012: 21
FWCI
13.82
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Institute of Mental Health (MH58880-03, P50MH058880)
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, bidirectional synaptic plasticity, long-term depression, long-term potentiation, working memory, episodic-like memory, reference memory, hippocampus, Schaffer collateral-CA1 synapses, contextual fear conditioning, Morris water maze, conditional gene targeting
MeSH terms
Animals, Conditioning, Psychological, Hippocampus, Learning, Male, Memory, Mice, Inbred C57BL, Neuronal Plasticity, Receptors, N-Methyl-D-Aspartate, In Situ Hybridization, Mice, Knockout, Gene Targeting, Patch-Clamp Techniques, Maze Learning, Calcineurin, Excitatory Postsynaptic Potentials, Protein Isoforms, Protein Subunits, Mice, In Vitro Techniques

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review