Hippocampal long-term depression and depotentiation are defective in mice carrying a targeted disruption of the gene encoding the RI beta subunit of cAMP-dependent protein kinase.
Open accessAbstract
The cAMP-dependent protein kinase (PKA) has been shown to play an important role in long-term potentiation (LTP) in the hippocampus, but little is known about the function of PKA in long-term depression (LTD). We have combined pharmacologic and genetic approaches to demonstrate that PKA activity is required for both homosynaptic LTD and depotentiation and that a specific neuronal isoform of type I regulatory subunit (RI beta) is essential. Mice carrying a null mutation in the gene encoding RI beta were established by use of gene targeting in embryonic stem cells. Hippocampal slices from mutant mice show a severe deficit in LTD and depotentiation at the Schaffer collateral-CA1 synapse. This defect is also evident at the lateral perforant path-dentate granule cell synapse in RI beta mutant mice. Despite a compensatory increase in the related RI alpha protein and a lack of detectable changes in total PKA activity, the hippocampal function in these mice is not rescued, suggesting a unique role for RI beta. Since the late phase of CA1 LTP also requires PKA but is normal in RI beta mutant mice, our data further suggest that different forms of synaptic plasticity are likely to employ different combinations of regulatory and catalytic subunits.
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.
Integrity signals
Registry
Cites
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.
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?
Spatial learning is apparently intact in knockout mice deficient in protein kinase A that lack CA1 LTD.
“However, we think that this is unlikely because spatial learning is apparently intact in knockout mice deficient in protein kinase A that lack CA1 LTD (Brandon et al., 1995).”
From The essential role of hippocampal CA1 NMDA receptor-dependent synaptic plasticity in spatial memory. (1996) · cites this paper as Brandon et al., 1995
The Abstract reports that RIβ-knockout mice have a severe deficit in LTD at the Schaffer collateral–CA1 synapse. It does not report a spatial-learning test or say that spatial learning is intact; its finding of normal CA1 LTP does not establish that part of the claim. (LLM, conf=0.87)
Experimental — accuracy not yet measuredLTD and depotentiation are sensitive to genetic manipulations of CaN and PKA expression, but their underlying signaling mechanisms are distinct.
“While LTD and depotentiation are sensitive to genetic manipulations of CaN and PKA expression, their underlying signaling mechanisms are distinct”
From AKAP150-Anchored Calcineurin Regulates Synaptic Plasticity by Limiting Synaptic Incorporation of Ca<sup>2+</sup>-Permeable AMPA Receptors (2012) · cites this paper as Brandon et al., 1995
The Abstract reports that mice lacking the PKA RIβ subunit have severe deficits in both LTD and depotentiation, supporting sensitivity to a genetic manipulation of PKA. Our copy does not report a genetic manipulation of calcineurin (CaN) or establish that LTD and depotentiation have distinct underlying signaling mechanisms; its statement about different forms of plasticity concerns LTD/depotentiation versus LTP. (LLM, conf=0.86)
Experimental — accuracy not yet measured
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
Effects of cAMP simulate a late stage of LTP in hippocampal CA1 neurons
Frey, U., Huang, Y.-Y., & Kandel, E. R. (1993) · Science · doi:10.1126/science.8389057 · Cited by 1,218 · see citing works
Involvement of a calcineurin/ inhibitor-1 phosphatase cascade in hippocampal long-term depression
Mulkey, R. M., Endo, S., Shenolikar, S., & Malenka, R. C. (1994) · Nature · doi:10.1038/369486a0 · Cited by 1,083 · see citing works
Synaptic plasticity in the hippocampus: LTP and LTD
Malenka, R. C. (1994) · Cell · doi:10.1016/0092-8674(94)90517-7 · Cited by 655 · see citing works
Rosenmund, C., Carr, D. W., Bergeson, S. E., Nilaver, G., Scott, J. D., & Westbrook, G. L. (1994) · Nature · doi:10.1038/368853a0 · Cited by 371 · see citing works
Flagged first, then by citations
Research works printed but not linked: 33
- Barrionuevo G., Schottler F., Lynch G. The effects of repetitive low frequency stimulation on control and "potentiated" synaptic responses in the hippocampus. Life Sci. 1980 Dec 15;27(24):2385–2391. doi: 10.1016/0024-3205(80)90509-3. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
- Bolshakov V. Y., Siegelbaum S. A. Postsynaptic induction and presynaptic expression of hippocampal long-term depression. Science. 1994 May 20;264(5162):1148–1152. doi: 10.1126/science.7909958. [DOI] [PubMed] [Google Scholar] · DOI
- Brandon E. P., Gerhold K. A., Qi M., McKnight G. S., Idzerda R. L. Derivation of novel embryonic stem cell lines and targeting of cyclic AMP-dependent protein kinase genes. Recent Prog Horm Res. 1995;50:403–408. doi: 10.1016/b978-0-12-571150-0.50028-7. [DOI] [PubMed] [Google Scholar] · DOI
- Cadd G. G., Uhler M. D., McKnight G. S. Holoenzymes of cAMP-dependent protein kinase containing the neural form of type I regulatory subunit have an increased sensitivity to cyclic nucleotides. J Biol Chem. 1990 Nov 15;265(32):19502–19506. [PubMed] [Google Scholar]
- Cadd G., McKnight G. S. Distinct patterns of cAMP-dependent protein kinase gene expression in mouse brain. Neuron. 1989 Jul;3(1):71–79. doi: 10.1016/0896-6273(89)90116-5. [DOI] [PubMed] [Google Scholar] · DOI
- Capecchi M. R. The new mouse genetics: altering the genome by gene targeting. Trends Genet. 1989 Mar;5(3):70–76. doi: 10.1016/0168-9525(89)90029-2. [DOI] [PubMed] [Google Scholar] · DOI
- Clegg C. H., Cadd G. G., McKnight G. S. Genetic characterization of a brain-specific form of the type I regulatory subunit of cAMP-dependent protein kinase. Proc Natl Acad Sci U S A. 1988 Jun;85(11):3703–3707. doi: 10.1073/pnas.85.11.3703. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- Clegg C. H., Correll L. A., Cadd G. G., McKnight G. S. Inhibition of intracellular cAMP-dependent protein kinase using mutant genes of the regulatory type I subunit. J Biol Chem. 1987 Sep 25;262(27):13111–13119. [PubMed] [Google Scholar]
- Dudek S. M., Bear M. F. Homosynaptic long-term depression in area CA1 of hippocampus and effects of N-methyl-D-aspartate receptor blockade. Proc Natl Acad Sci U S A. 1992 May 15;89(10):4363–4367. doi: 10.1073/pnas.89.10.4363. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page
- Frank D. A., Greenberg M. E. CREB: a mediator of long-term memory from mollusks to mammals. Cell. 1994 Oct 7;79(1):5–8. doi: 10.1016/0092-8674(94)90394-8. [DOI] [PubMed] [Google Scholar] · DOI
- Fujii S., Saito K., Miyakawa H., Ito K., Kato H. Reversal of long-term potentiation (depotentiation) induced by tetanus stimulation of the input to CA1 neurons of guinea pig hippocampal slices. Brain Res. 1991 Jul 26;555(1):112–122. doi: 10.1016/0006-8993(91)90867-u. [DOI] [PubMed] [Google Scholar] · DOI
- Hell J. W., Yokoyama C. T., Wong S. T., Warner C., Snutch T. P., Catterall W. A. Differential phosphorylation of two size forms of the neuronal class C L-type calcium channel alpha 1 subunit. J Biol Chem. 1993 Sep 15;268(26):19451–19457. [PubMed] [Google Scholar]
- Huang Y. Y., Kandel E. R. Recruitment of long-lasting and protein kinase A-dependent long-term potentiation in the CA1 region of hippocampus requires repeated tetanization. Learn Mem. 1994 May-Jun;1(1):74–82. [PubMed] [Google Scholar]
- Huang Y. Y., Li X. C., Kandel E. R. cAMP contributes to mossy fiber LTP by initiating both a covalently mediated early phase and macromolecular synthesis-dependent late phase. Cell. 1994 Oct 7;79(1):69–79. doi: 10.1016/0092-8674(94)90401-4. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
- Johnson B. D., Scheuer T., Catterall W. A. Voltage-dependent potentiation of L-type Ca2+ channels in skeletal muscle cells requires anchored cAMP-dependent protein kinase. Proc Natl Acad Sci U S A. 1994 Nov 22;91(24):11492–11496. doi: 10.1073/pnas.91.24.11492. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- Kirkwood A., Bear M. F. Homosynaptic long-term depression in the visual cortex. J Neurosci. 1994 May;14(5 Pt 2):3404–3412. doi: 10.1523/JNEUROSCI.14-05-03404.1994. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- Larson J., Xiao P., Lynch G. Reversal of LTP by theta frequency stimulation. Brain Res. 1993 Jan 8;600(1):97–102. doi: 10.1016/0006-8993(93)90406-d. [DOI] [PubMed] [Google Scholar] · DOI
- Linden D. J. Long-term synaptic depression in the mammalian brain. Neuron. 1994 Mar;12(3):457–472. doi: 10.1016/0896-6273(94)90205-4. [DOI] [PubMed] [Google Scholar] · DOI
- Lisman J. A mechanism for the Hebb and the anti-Hebb processes underlying learning and memory. Proc Natl Acad Sci U S A. 1989 Dec;86(23):9574–9578. doi: 10.1073/pnas.86.23.9574. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page
- Massa J. S., Walker P. S., Moser D. R., Fellows R. E., Maurer R. A. Fetal development and neuronal/glial cell specificity of cAMP-dependent protein kinase subunit mRNAs in rat brain. Dev Neurosci. 1991;13(1):47–53. doi: 10.1159/000112140. [DOI] [PubMed] [Google Scholar] · DOI
- Matthies H., Reymann K. G. Protein kinase A inhibitors prevent the maintenance of hippocampal long-term potentiation. Neuroreport. 1993 Jun;4(6):712–714. doi: 10.1097/00001756-199306000-00028. [DOI] [PubMed] [Google Scholar] · DOI
- McKnight G. S., Clegg C. H., Uhler M. D., Chrivia J. C., Cadd G. G., Correll L. A., Otten A. D. Analysis of the cAMP-dependent protein kinase system using molecular genetic approaches. Recent Prog Horm Res. 1988;44:307–335. doi: 10.1016/b978-0-12-571144-9.50014-4. [DOI] [PubMed] [Google Scholar] · DOI
- Mulkey R. M., Herron C. E., Malenka R. C. An essential role for protein phosphatases in hippocampal long-term depression. Science. 1993 Aug 20;261(5124):1051–1055. doi: 10.1126/science.8394601. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
- Mulkey R. M., Malenka R. C. Mechanisms underlying induction of homosynaptic long-term depression in area CA1 of the hippocampus. Neuron. 1992 Nov;9(5):967–975. doi: 10.1016/0896-6273(92)90248-c. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
- O'Dell T. J., Kandel E. R. Low-frequency stimulation erases LTP through an NMDA receptor-mediated activation of protein phosphatases. Learn Mem. 1994 Jul-Aug;1(2):129–139. [PubMed] [Google Scholar]
- Ramírez-Solis R., Davis A. C., Bradley A. Gene targeting in embryonic stem cells. Methods Enzymol. 1993;225:855–878. doi: 10.1016/0076-6879(93)25054-6. [DOI] [PubMed] [Google Scholar] · DOI
- Raymond L. A., Blackstone C. D., Huganir R. L. Phosphorylation of amino acid neurotransmitter receptors in synaptic plasticity. Trends Neurosci. 1993 Apr;16(4):147–153. doi: 10.1016/0166-2236(93)90123-4. [DOI] [PubMed] [Google Scholar] · DOI
- Rogers K. V., Boring L. F., McKnight G. S., Clegg C. H. Promoter for the regulatory type I beta subunit of the 3',5'-cyclic adenosine monophosphate-dependent protein kinase directs transgene expression in the central nervous system. Mol Endocrinol. 1992 Oct;6(10):1756–1765. doi: 10.1210/mend.6.10.1448119. [DOI] [PubMed] [Google Scholar] · DOI
- Skålhegg B. S., Taskén K., Hansson V., Huitfeldt H. S., Jahnsen T., Lea T. Location of cAMP-dependent protein kinase type I with the TCR-CD3 complex. Science. 1994 Jan 7;263(5143):84–87. doi: 10.1126/science.8272870. [DOI] [PubMed] [Google Scholar] · DOI
- Solberg R., Taskén K., Wen W., Coghlan V. M., Meinkoth J. L., Scott J. D., Jahnsen T., Taylor S. S. Human regulatory subunit RI beta of cAMP-dependent protein kinases: expression, holoenzyme formation and microinjection into living cells. Exp Cell Res. 1994 Oct;214(2):595–605. doi: 10.1006/excr.1994.1297. [DOI] [PubMed] [Google Scholar] · DOI
- Staubli U., Lynch G. Stable depression of potentiated synaptic responses in the hippocampus with 1-5 Hz stimulation. Brain Res. 1990 Apr 9;513(1):113–118. doi: 10.1016/0006-8993(90)91096-y. [DOI] [PubMed] [Google Scholar] · DOI
- Yan C., Bentley J. K., Sonnenburg W. K., Beavo J. A. Differential expression of the 61 kDa and 63 kDa calmodulin-dependent phosphodiesterases in the mouse brain. J Neurosci. 1994 Mar;14(3 Pt 1):973–984. doi: 10.1523/JNEUROSCI.14-03-00973.1994. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- Yang X. D., Connor J. A., Faber D. S. Weak excitation and simultaneous inhibition induce long-term depression in hippocampal CA1 neurons. J Neurophysiol. 1994 Apr;71(4):1586–1590. doi: 10.1152/jn.1994.71.4.1586. [DOI] [PubMed] [Google Scholar] · DOI
Cited by
Sorted by citations
The essential role of hippocampal CA1 NMDA receptor-dependent synaptic plasticity in spatial memory.
Tsien, J. Z., Huerta, P. T., & Tonegawa, S. (1996) · Cell · doi:10.1016/s0092-8674(00)81827-9 · Cited by 1,782 · see citing works
Long-term depression in the CNS
Collingridge, G. L., Peineau, S., Howland, J. G., & Wang, Y. T. (2010) · Nature Reviews Neuroscience · doi:10.1038/nrn2867 · Cited by 926 · see citing works
The role of CREB signaling in Alzheimer’s disease and other cognitive disorders
Saura, C. A., & Valero, J. (2011) · revneuro · doi:10.1515/rns.2011.018 · Cited by 312 · see citing works
Huang, Y.-Y., Kandel, E. R., Varshavsky, L., Brandont, E. P., Qi, M., Idzerda, R. L., Stanley McKnight, G., & Bourtchouladz, R. (1995) · Cell · doi:10.1016/0092-8674(95)90146-9 · Cited by 267 · see citing works
Self-citationType I Adenylyl Cyclase Mutant Mice Have Impaired Mossy Fiber Long-Term Potentiation
Villacres, E. C., Wong, S. T., Chavkin, C., & Storm, D. R. (1998) · The Journal of Neuroscience · doi:10.1523/jneurosci.18-09-03186.1998 · Cited by 187 · see citing works
“For example, mutant mice lacking the R1b subunit of PKA show a compensating increase in the R1a subunit (Brandon et al., 1995).”
BackgroundAltered Stress-Induced Anxiety in Adenylyl Cyclase Type VIII-Deficient Mice
Schaefer, M. L., Wong, S. T., Wozniak, D. F., Muglia, L. M., Liauw, J. A., Zhuo, M., Nardi, A., Hartman, R. E., Vogt, S. K., Luedke, C. E., et al. (2000) · The Journal of Neuroscience · doi:10.1523/jneurosci.20-13-04809.2000 · Cited by 152 · see citing works
Self-citationRegulation of NMDA receptor Ca2+ signalling and synaptic plasticity
Lau, C. G., Takeuchi, K., Rodenas-Ruano, A., Takayasu, Y., Murphy, J., Bennett, M. V. L., & Zukin, R. S. (2009) · Biochemical Society Transactions · doi:10.1042/bst0371369 · Cited by 138 · see citing works
Sanderson, J. L., Gorski, J. A., Gibson, E. S., Lam, P., Freund, R. K., Chick, W. S., & Dell'Acqua, M. L. (2012) · The Journal of Neuroscience · doi:10.1523/jneurosci.3326-12.2012 · Cited by 137 · see citing works
Hensch, T. K., Gordon, J. A., Brandon, E. P., McKnight, G. S., Idzerda, R. L., & Stryker, M. P. (1998) · The Journal of Neuroscience · doi:10.1523/jneurosci.18-06-02108.1998 · Cited by 117 · see citing works
Self-citationWolff, G. H., & Strausfeld, N. J. (2016) · Philosophical Transactions of the Royal Society B: Biological Sciences · doi:10.1098/rstb.2015.0055 · Cited by 61 · see citing works
- Authors
- Brandon, E. P., Zhuo, M., Huang, Y. Y., Qi, M., Gerhold, K. A., Burton, K. A., Kandel, E. R., McKnight, G. S., & Idzerda, R. L.
- Affiliations
- University of Washington (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 1995-09-12
- Volume
- 92
- Issue
- 19
- Pages
- 8851-8855
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC41065
- OpenAlex
- W2089083186
- Cited by
- 216
- References
- 4
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 2 · 2023: 4 · 2022: 2 · 2021: 4 · 2020: 8 · 2019: 3 · 2018: 5 · 2017: 4 · 2016: 1 · 2015: 3 · 2014: 5 · 2013: 8 · 2012: 6
- FWCI
- 5.07
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5t32gm007108-40, 5p01gm032099-14)
- National Institute of General Medical Sciences (GM 32099, GM-07108, GM32875, R01GM032875)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- protein kinase A, long-term depression, depotentiation, hippocampus, Schaffer collateral-CA1 synapses, synaptic plasticity, long-term potentiation, gene targeting, null mutations
- MeSH terms
- Animals, Electrophysiology, Hippocampus, Homozygote, Mice, Mutant Strains, Mice, Transgenic, Neuronal Plasticity, RNA, Messenger, Synapses, Signal Transduction, Cyclic AMP-Dependent Protein Kinases, Mice, Cyclic AMP-Dependent Protein Kinase RIbeta Subunit, 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
