Article | Published:

Metaplasticity contributes to memory formation in the hippocampus

Neuropsychopharmacologyvolume 44pages408414 (2019) | Download Citation


Prior learning can modify the plasticity mechanisms that are used to encode new information. For example, NMDA receptor (NMDAR) activation is typically required for new spatial and contextual learning in the hippocampus. However, once animals have acquired this information, they can learn new tasks even if NMDARs are blocked. This finding suggests that behavioral training alters cellular plasticity mechanisms such that NMDARs are not required for subsequent learning. The mechanisms that mediate this change are currently unknown. To address this issue, we tested the idea that changes in intrinsic excitability (induced by learning) facilitate the encoding of new memories via metabotropic glutamate receptor (mGluR) activation. Consistent with this hypothesis, hippocampal neurons exhibited increases in intrinsic excitability after learning that lasted for several days. This increase was selective and only observed in neurons that were activated by the learning event. When animals were trained on a new task during this period, excitable neurons were reactivated and memory formation required the activation of mGluRs instead of NMDARs. These data suggest that increases in intrinsic excitability may serve as a metaplastic mechanism for memory formation.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Additional information

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


  1. 1.

    Bouton ME. Context, time, and memory retrieval in the interference paradigms of pavlovian learning. Psychol Bull. 1993;114:80–99.

  2. 2.

    Winocur G. The effects of retroactive and proactive interference on learning and memory in old and young rats. Dev Psychobiol. 1984;17:537–45.

  3. 3.

    Tse D, Langston RF, Kakeyama M, Bethus I, Spooner PA, Wood ER, et al. Schemas and memory consolidation. Science. 2007;316:76–82.

  4. 4.

    Tse D, Takeuchi T, Kakeyama M, Kajii Y, Okuno H, Tohyama C, et al. Schema-dependent gene activation and memory encoding in neocortex. Science. 2011;333:891–5.

  5. 5.

    Saucier D, Cain DP. Spatial learning without NMDA receptor-dependent long-term potentiation. Nature. 1995;378:186–9.

  6. 6.

    Bannerman DM, Good MA, Butcher SP, Ramsay M, Morris RGM. Distinct components of spatial learning revealed by prior training and NMDA receptor blockade. Nature. 1995;378:182–6.

  7. 7.

    Quinlan EM, Lebel D, Brosh I, Barkai E. A molecular mechanism for stabilization of learning-induced synaptic modifications. Neuron. 2004;41:185–92.

  8. 8.

    Sanders MJ, Fanselow MS. Pre-training prevents context fear conditioning deficits produced by hippocampal NMDA receptor blockade. Neurobiol Learn Mem. 2003;80:123–9.

  9. 9.

    Tayler KK, Lowry E, Tanaka K, Levy B, Reijmers L, Mayford M, et al. Characterization of NMDAR-independent learning in the hippocampus. Front Behav Neurosci. 2011;5:1–12.

  10. 10.

    Wiltgen BJ, Royle GA, Gray EE, Abdipranoto A, Thangthaeng N, Jacobs N, et al. A role for calcium-permeable AMPA receptors in synaptic plasticity and learning. PLoS ONE. 2010;4:158,1–11.

  11. 11.

    Wiltgen BJ, Wood AN, Levy B. The cellular mechanisms of memory are modified by experience. Learn Mem. 2011;18:747–50.

  12. 12.

    Cai DJ, Aharoni D, Shuman T, Shobe J, Biane J, Song W, et al. A shared neural ensemble links distinct contextual memories encoded close in time. Nature. 2016;534:115–8.

  13. 13.

    Chandra N, Barkai E. A non-synaptic mechanism of complex learning: modulation of intrinsic neuronal excitability. Neurobiol Learn Mem. 2017.

  14. 14.

    Moyer JR, Thompson LT, Disterhoft JF. Trace eyeblink conditioning increases CA1 excitability in a transient and learning-specific manner. J Neurosci. 1996;16:5536–46.

  15. 15.

    Saar D, Barkai E. Long-term modifications in intrinsic neuronal properties and rule learning in rats. Eur J Neurosci. 2003;17:2727–34.

  16. 16.

    Nicoll RA, Schmitz D. Synaptic plasticity at hippocampal mossy fibre synapses. Nat Rev Neurosci. 2005;6:863–76.

  17. 17.

    Wang H, Ardiles AO, Yang S, Tran T, Posada-Duque R, Valdivia G, et al. Metabotropic glutamate receptors induce a form of LTP controlled by translation and Arc signaling in the hippocampus. J Neurosci. 2016;36:1723–9.

  18. 18.

    Reijmers LG, Mayford M. Genetic control of active neural circuits. Front Mol Neurosci. 2009;2:1–8.

  19. 19.

    Ting JT, Daigle TL, Chen Q, Feng G. Acute brain slice methods for adult and aging animals: application of targeted patch clamp analysis and optogenetics. Methods Mol Biol. 2014;1183:221–42.

  20. 20.

    Nakazawa Y, Pevzner A, Tanaka KZ, Wiltgen BJ. Memory retrieval along the proximodistal axis of CA1. Hippocampus. 2016;26:1140–8.

  21. 21.

    Tanaka KZ, Pevzner A, Hamidi AB, Nakazawa Y, Graham J, Wiltgen BJ. Cortical representations are reinstated by the hippocampus during memory retrieval. Neuron. 2014;84:347–54.

  22. 22.

    Dong HW. The Allen reference atlas: a digital color brain atlas of the C57Bl/6J male mouse. Hoboken, NJ: USJohn Wiley Sons Inc.; 2008.

  23. 23.

    Ramirez S, Liu X, Lin P-A, Suh J, Pignatelli M, Redondo RL, et al. Creating a false memory in the hippocampus. Science. 2013;341:387–91.

  24. 24.

    Anagnostaras SG. Automated assessment of Pavlovian conditioned freezing and shock reactivity in mice using the VideoFreeze system. Front Behav Neurosci. 2010;5-e12818,1–18.

  25. 25.

    Clem RL, Celike T, Barth AL. Ongoing in vivo experience triggers synaptic metaplasticity in the neocortex. Science. 2008;319:101–4.

  26. 26.

    Wang S-H, Redondo RL, Morris RGM. Relevance of synaptic tagging and capture to the persistence of long-term potentiation and everyday spatial memory. Proc Natl Acad Sci USA. 2010;107:19537–42.

  27. 27.

    Elgersma Y, Silva aJ. Molecular mechanisms of synaptic plasticity and memory. Curr Opin Neurobiol. 1999;9:209–13.

  28. 28.

    Morris RGM, Davis S, Butcher SP. Hippocampal synaptic plasticity and NMDA receptors: a role in information storage? Philos Trans R Soc B Biol Sci. 1990;329:187–204.

  29. 29.

    Thompson LT, Moyer JR, Disterhoft JF. Transient changes in excitability of rabbit CA3 neurons with a time course appropriate to support memory consolidation. J Neurophysiol. 1996;76:1836–49.

  30. 30.

    Crestani AP,Sierra RO,Machado A,Haubrich J,Scienza KM,de Oliveira Alvares L, et al. Hippocampal plasticity mechanisms mediating experience-dependent learning change over time. Neurobiol Learn Mem. 2018;150:56–63.

  31. 31.

    Choi J-H, Sim S-E, Kim J-I, Choi DIl, Oh J, Ye S, et al. Interregional synaptic maps among engram cells underlie memory formation. Science. 2018;360:430–5.

  32. 32.

    Gray JA, Shi Y, Usui H, During MJ, Sakimura K, Nicoll RA. Distinct modes of AMPA receptor suppression at developing synapses by GluN2A and GluN2B: single-cell NMDA receptor subunit deletion in vivo. Neuron. 2011;71:1085–101.

  33. 33.

    Philpot BD, Cho KKA, Bear MF. Obligatory role of NR2A for metaplasticity in visual cortex. Neuron. 2007;53:495–502.

  34. 34.

    Quinlan EM, Philpot BD, Huganir RL, Bear MF. Rapid, experience-dependent expression of synaptic NMDA receptors in visual cortex in vivo. Nat Neurosci. 1999;2:352–7.

  35. 35.

    Wang SH, Finnie PSB, Hardt O, Nader K. Dorsal hippocampus is necessary for novel learning but sufficient for subsequent similar learning. Hippocampus. 2012;22:2157–70.

  36. 36.

    Franklin KBJ, Paxinos G. The mouse brain in stereotaxic coordinates. Amsterdam: Elsevier Academic Press; 2008.

  37. 37.

    Oh WC, Hill TC, Zito K. Synapse-specific and size-dependent mechanisms of spine structural plasticity accompanying synaptic weakening. Proc Natl Acad Sci U S A. 2013;110:E305–E312.

Download references


These experiments were supported by a Whitehall Foundation Research Grant to B.J.W. and a CNPq/Brazil graduate fellowship to A.P.C. “SWE Process: 202250/2015-6”.

Author information

Author notes

  1. These authors contributed equally: Ana P. Crestani, Jamie N. Krueger


  1. Neuroscience Graduate Program, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil

    • Ana P. Crestani
  2. Neuroscience Graduate Program, University of California, Davis, Davis, CA, USA

    • Jamie N. Krueger
    •  & Eden V. Barragan
  3. Center for Neuroscience, University of California, Davis, Davis, CA, USA

    • Yuki Nakazawa
    • , John A. Gray
    •  & Brian J. Wiltgen
  4. Department of Neurobiology, Physiology and Behavior, University of California, Davis, Davis, CA, USA

    • Sonya E. Nemes
  5. Department of Biophysics, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil

    • Jorge A. Quillfeldt
  6. Department of Neurology, University of California, Davis, Davis, CA, USA

    • John A. Gray
  7. Department of Psychology, University of California, Davis, Davis, CA, USA

    • Brian J. Wiltgen


  1. Search for Ana P. Crestani in:

  2. Search for Jamie N. Krueger in:

  3. Search for Eden V. Barragan in:

  4. Search for Yuki Nakazawa in:

  5. Search for Sonya E. Nemes in:

  6. Search for Jorge A. Quillfeldt in:

  7. Search for John A. Gray in:

  8. Search for Brian J. Wiltgen in:

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Brian J. Wiltgen.

About this article

Publication history





Issue Date


Further reading