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 GluA2 3Y or G2CT in the dorsal hippocampus during a memory retention interval prevented the normal forgetting of established, longterm 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 GluA2 3Y 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 GluA2 3Y 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.

The genetics of PKMζ and memory maintenance

“…PKMζ increases postsynaptic receptors by decreasing postsynaptic AMPAR endocytosis mediated by the trafficking protein N -ethylmaleimide–sensitive factor (NSF) through action on the GluA2 subunit of the receptor (35). Further evidence indicates that this mechanism of postsynaptic potentiation maintains both late LTP and long-term memory storage (35–39). …”

Coordination of AMPA receptor trafficking by Rab GTPases

“…77,79 Thus, the lack of RIN1 leads to increased amount of AMPARs at the plasma membrane, which cannot be downregulated upon NMDA-dependent cLTD. Because AMPAR downregulation is required during fear extinction in the amygdala, 80,81 one interesting possibility is that prolonged fear memory of RIN1 ¡/¡ mice as well as their inability to forget aversive memories are due to the increased surface level of AMPARs and the inability to downregulate their levels during LTD and fear extinction through Rab5-dependent endocytosis.…”

Lost and found

“…Effective forgetting is also central to effective memory. Three new neurobiological papers have recently been published that highlight different aspects of forgetting (Madronal et al, 2016, Migues et al, 2016, Roy et al, 2016.…”

“…The idea that forgetting may be an active process is also the key theme of the work of Migues et al (2016). Adopting a more biochemical perspective linked in part to the work of Todd Sacktor in New York, e.g.…”

“…However, a drug is unlikely 'to do it on its own' without appropriate stimulation. In the same vein, Madronal et al (2016) and Migues et al (2016) emphasise that the 'devil-is-in-the-detail' with a respect to understanding activity-dependent forgetting. It is likely some way off, but these neurobiological studies raise, in different ways, the intriguing idea of rescuing long-term memory deficits, with a peptide or another engrambased approach, in a manner that takes account of this neuronal activity and selectivity.…”