Blocking synaptic removal of GluA2-containing AMPA receptors prevents the natural forgetting of long-term memories
Open accessAbstract
The neurobiological processes underpinning the natural forgetting of long-term memories are poorly understood. Based on the critical role of GluA2-containing AMPA receptors (GluA2/AMPARs) in long-term memory persistence, we tested in rats whether their synaptic removal underpins time-dependent memory loss. We found that blocking GluA2/AMPAR removal with the interference peptides GluA23Y or G2CT in the dorsal hippocampus during a memory retention interval prevented the normal forgetting of established, long-term object location memories, but did not affect their acquisition. The same intervention also preserved associative memories of food-reward conditioned place preference that would otherwise be lost over time. We then explored whether this forgetting process could play a part in behavioral phenomena involving time-dependent memory change. We found that infusing GluA23Y into the dorsal hippocampus during a 2 week retention interval blocked generalization of contextual fear expression, whereas infusing it into the infralimbic cortex after extinction of auditory fear prevented spontaneous recovery of the conditioned response. Exploring possible physiological mechanisms that could be involved in this form of memory decay, we found that bath application of GluA23Y prevented depotentiation, but not induction of long-term potentiation, in a hippocampal slice preparation. Together, these findings suggest that a decay-like forgetting process that involves the synaptic removal of GluA2/AMPARs erases consolidated long-term memories in the hippocampus and other brain structures over time. This well regulated forgetting process may critically contribute to establishing adaptive behavior, whereas its dysregulation could promote the decline of memory and cognition in neuropathological disorders. SIGNIFICANCE STATEMENT: The neurobiological mechanisms involved in the natural forgetting of long-term memory and its possible functions are not fully understood. Based on our previous work describing the role of GluA2-containing AMPA receptors in memory maintenance, here, we tested their role in forgetting of long-term memory. We found that blocking their synaptic removal after long-term memory formation extended the natural lifetime of several forms of memory. In the hippocampus, it preserved spatial memories and inhibited contextual fear generalization; in the infralimbic cortex, it blocked the spontaneous recovery of extinguished fear. These findings suggest that a constitutive decay-like forgetting process erases long-term memories over time, which, depending on the memory removed, may critically contribute to developing adaptive behavioral responses.
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Post-sample hippocampal infusions of GluA23Y or G2CT that interfered with GluA2/AMPA-R removal reinstated forgotten OPP long-term memory and did not influence new OPP learning.
“post-sample hippocampal infusions of GluA23Y or G2CT that interfered with the GluA2/AMPA-R removal, reinstated the forgotten OPP long-term memory and did not influence new OPP learning”
From The medial prefrontal cortex - hippocampus circuit that integrates information of object, place and time to construct episodic memory in rodents: Behavioral, anatomical and neurochemical properties (2020) · cites this paper as Migues et al., 2016
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Self-citation
- Authors
- Migues, P. V., Liu, L., Archbold, G. E. B., Einarsson, E. Ö., Wong, J., Bonasia, K., Ko, S. H., Wang, Y. T., & Hardt, O.
- Affiliations
- University of Edinburgh (GB)
- University of British Columbia (CA)
- McGill University (CA)
- Inserm (FR)
- University of Toronto (CA)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2016-03-23
- Volume
- 36
- Issue
- 12
- Pages
- 3481-3494
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6601735
- OpenAlex
- W2304552143
- Cited by
- 153
- References
- 63
- Citations by year
- 2026: 7 · 2025: 9 · 2024: 13 · 2023: 5 · 2022: 14 · 2021: 25 · 2020: 19 · 2019: 26 · 2018: 15 · 2017: 11 · 2016: 9
- FWCI
- 12.90
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- Funders
- Heart and Stroke Foundation of Canada
- Wellcome Trust
- Canadian Institutes of Health Research
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory Processes and Influences
- Keywords
- forgetting, object location memory, conditioned place preference, fear extinction, spontaneous recovery, depotentiation, long-term potentiation, hippocampus, infralimbic cortex, memory decay
- MeSH terms
- Animals, Male, Neuronal Plasticity, Mental Recall, Reward, Stereotyped Behavior, Synapses, Receptors, AMPA, Rats, Long-Evans, Rats, Memory, Long-Term
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