Blocking Synaptic Removal of GluA2-Containing AMPA Receptors Prevents the Natural Forgetting of Long-Term Memories.

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.

Evidence for the persistence of contextual fear memories following immediate extinction.

Evidence suggests that extinction, the suppression of a learned response to a Pavlovian signal that is produced by exposure to the signal alone after conditioning, is a consequence of new inhibitory learning. However, it has been proposed that extinction given immediately after conditioning reflects memory 'erasure'. Using contextual fear conditioning, we examine the nature of extinction further using a novel behavioral paradigm that probes for the absence or presence of a memory. Rats received a context paired with one of three different shock intensities (0.8, 1.2 or 1.6 mA) and then received extinction either immediately (15 min) or after a delay (24 h). Spontaneous recovery was roughly equivalent in the immediate and delayed extinction groups when they were tested at 24 h after extinction. To further test the status of the original memory trace, we exploited the effect that only the first, but not second, learning of contextual fear requires N-methyl-D-aspartate receptors (NMDArs) in the dorsal hippocampus [M.J. Sanders & M.S. Fanselow (2003) Neurobiology of Learning and Memory 80,123-129]. Here we use this property of second learning to determine if memory of an immediately extinguished fear also persists. Rats received bilateral infusions of the NMDAr antagonist DL-2-amino-5-phosphonopentanoic acid into the dorsal hippocampus prior to training in a novel second context. Memory for the second learning is not affected by NMDAr blockade in either group, suggesting that the extinguished memory is not erased but inhibited. Overall, the results provide little evidence that extinction conducted immediately after conditioning destroys or erases the original memory trace.