title: Blocking Synaptic Removal of GluA2-Containing AMPA Receptors Prevents the Natural Forgetting of Long-Term Memories.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Centre for Cognitive and Neural Systems, The University of Edinburgh, Edinburgh EH8 9JZ, United Kingdom.
authors.forename: Paola Virginia
authors.initials: PV
authors.lastname: Migues
authors.affiliation: University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada.
authors.forename: Lidong
authors.initials: L
authors.lastname: Liu
authors.affiliation: McGill University, Montreal, Quebec H3A 1B1, Canada.
authors.forename: Georgina E B
authors.initials: GE
authors.lastname: Archbold
authors.affiliation: INSERM U862, Neurocenter Magendie, 33077 Bordeaux, France.
authors.forename: Einar Ö
authors.identifier: http://orcid.org/0000-0001-5058-0312
authors.initials: EÖ
authors.lastname: Einarsson
authors.affiliation: McGill University, Montreal, Quebec H3A 1B1, Canada.
authors.forename: Jacinda
authors.initials: J
authors.lastname: Wong
authors.affiliation: University of Toronto, Toronto, Ontario M5S 3G3, Canada, and.
authors.forename: Kyra
authors.identifier: http://orcid.org/0000-0002-2972-581X
authors.initials: K
authors.lastname: Bonasia
authors.affiliation: McGill University, Montreal, Quebec H3A 1B1, Canada.
authors.forename: Seung Hyun
authors.initials: SH
authors.lastname: Ko
authors.affiliation: University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada, China Medical University Hospital, China Medical University, Taichung, Taiwan 40402.
authors.forename: Yu Tian
authors.initials: YT
authors.lastname: Wang
authors.affiliation: Centre for Cognitive and Neural Systems, The University of Edinburgh, Edinburgh EH8 9JZ, United Kingdom, oliver.hardt@ed.ac.uk.
authors.forename: Oliver
authors.identifier: http://orcid.org/0000-0002-3975-9634
authors.initials: O
authors.lastname: Hardt
mesh_terms: D000818:Animals; D008297:Male; D057567:Memory, Long-Term / Q000502:physiology*; D011939:Mental Recall / Q000502:physiology*; D009473:Neuronal Plasticity / Q000502:physiology*; D051381:Rats; D020318:Rats, Long-Evans; D018091:Receptors, AMPA / Q000378:metabolism*; D012201:Reward; D013239:Stereotyped Behavior / Q000502:physiology; D013569:Synapses / Q000502:physiology*
chemical_list: D018091:Receptors, AMPA; C104722:glutamate receptor ionotropic, AMPA 2
keywords: decay; forgetting; long-term memory