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.

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.

Evidence suggests that extinction is new learning. Memory acquisition involves both short-term memory (STM) and longterm memory (LTM) components; however, few studies have examined early phases of extinction retention. Retention of auditory fear extinction was examined at various time points. Shortly (1 -4 h) after extinction acquisition spontaneous recovery was high compared to that after longer delays (8 -24 h). Recall of a consolidated extinction trace was also impaired if it was preceded 1 h by extinction of a novel CS; propranolol did not attenuate this effect. These results suggest poor extinction retention reflects a retrieval impairment caused by the aversive experience of extinction training.In Pavlovian fear conditioning pairing a neutral stimulus with an unconditioned aversive stimulus (US) results in conditioned learning, whereby the previously neutral stimulus comes to elicit fear responses. Conversely, the conditioned stimulus (CS) repeatedly presented in the absence of the US leads to reduction of the fear behavior known as extinction (Pavlov 1927). Although there has been some debate over the exact nature of extinction, it is widely accepted that this phenomenon is new learning rather than unlearning of the original association (Rescorla 1997;Bouton 2004). Return of the extinguished behavior is observed in tests of spontaneous recovery (Pavlov 1927), renewal (Bouton andKing 1983), and reinstatement (Rescorla and Heth 1975;Bouton and Bolles 1979).Both behavioral (McGaugh 1966) and molecular (Kandel 2001) studies suggest that following learning there are two distinct phases of memory: short-term memory (STM) and long-term memory (LTM). STM, lasting on the order of minutes to hours, involves covalent modifications of preexisting proteins, while LTM is much less transient and involves protein synthesis, new gene expression, and changes in synaptic structure. Disruption of protein synthesis following learning leads to impairments in LTM retention while sparing STM (Davis and Squire 1984). STM for fear extinction is often considered to be the within-session responding during extinction training, whereas LTM for fear extinction is measured by successful extinction recall usually tested upward of 24 h (Quirk 2002). Tests of long-term extinction memory are frequently used to measure spontaneous recovery, the return of the original trace that occurs with the passage of time; more recovery is observed with increasing delays between extinction and test (Pavlov 1927;Ellson 1939;Burdick and James 1970;Robbins 1990). Surprisingly, few studies have tested memory for fear extinction within 24 h of extinction acquisition. Berman et al. (2003) explored the time course of an extinguished conditioned taste aversion (CTA) memory, testing retention of extinction at intervals as short as 30 min following extinction. They found that the extinguished behavior was not evident shortly after extinction but became apparent with a delay of 2 h. The authors further determined that the absence of extinction shortly after extinct...