NMDA receptor activity bidirectionally controls active decay of long-term spatial memory in the dorsal hippocampus.

The time-dependent forgetting of long-term spatial memories involves activation of NMDA receptors (NMDARs) in the hippocampus. Here, we tested whether NMDARs regulate memory persistence bidirectionally, decreasing or increasing the rate of forgetting. We found that blocking NMDAR activation with AP5 or the GluN2B-selective antagonist Ro25-6981 in the dorsal hippocampus (dHPC) prevented the natural forgetting of long-term memory for the locations of objects in an open field arena. In contrast, while enhancing NMDAR function with the partial agonist D-Cycloserine did not affect the speed of forgetting for these types of memories, infusing the NMDAR co-agonist D-Serine significantly shortened their persistence. These results suggest that NMDAR activity can modulate the speed of constitutive long-term memory decay in the dHPC and that regulating NMDAR expression and D-Serine availability could provide a mechanism to control the duration of long-term memory.

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.

PKMzeta maintains 1-day- and 6-day-old long-term object location but not object identity memory in dorsal hippocampus.

Continuous activity of the atypical protein kinase C isoform M zeta (PKMzeta) is necessary for maintaining long-term memory acquired in aversively or appetitively motivated associative learning tasks, such as active avoidance, aversive taste conditioning, auditory and contextual fear conditioning, radial arm maze, and watermaze. Whether unreinforced, nonassociative memory will also require PKMzeta for long-term maintenance is not known. Using recognition memory for object location and object identity, we found that inactivating PKMzeta in dorsal hippocampus abolishes 1-day and 6-day-old long-term recognition memory for object location, while recognition memory for object identity was not affected by this treatment. Memory for object location persisted for no more than 35 days after training. These results suggest that the dorsal hippocampus mediates long-term memory for where, but not what things have been encountered, and that PKMzeta maintains this type of spatial knowledge as long as the memory exists.