Abstract
Extinction memory destabilized by recall is restabilized through mTOR-dependent reconsolidation in the hippocampus, but the upstream pathways controlling these processes remain unknown. Hippocampal NMDARs drive local protein synthesis via mTOR signaling and may control active memory maintenance. We found that in adult male Wistar rats, intra dorsal-CA1 administration of the non-subunit selective NMDAR antagonist AP5 or of the GluN2A subunit-containing NMDAR antagonist TCN201 after step down inhibitory avoidance (SDIA) extinction memory recall impaired extinction memory retention and caused SDIA memory recovery. On the contrary, pre-recall administration of AP5 or of the GluN2B subunit-containing NMDAR antagonist RO25-6981 had no effect on extinction memory recall or retention per se but hindered the recovery of the avoidance response induced by post-recall intra-CA1 infusion of the mTOR inhibitor rapamycin. Our results indicate that GluN2B-containing NMDARs are necessary for extinction memory destabilization whereas GluN2A-containing NMDARs are involved in its restabilization, and suggest that pharmacological modulation of the relative activation state of these receptor subtypes around the moment of extinction memory recall may regulate the dominance of extinction memory over the original memory trace.
Highlights
Recall reactivates memories that lay dormant and may affect their strength and endurance
To study the role of hippocampal N-methyl-D-aspartic acid receptors (NMDARs) in the reconsolidation of extinction memory, we first trained adult male Wistar rats in one-trial step-down inhibitory avoidance (SDIA; 0.4 mA/2 s foot shock), a learning task that induces a long-lasting hippocampus dependent fear-motivated avoidance m emory[14,15] and beginning one day post-training, we reexposed the animals to the SDIA training apparatus in the absence of the foot shock once daily for 5 consecutive days
Our data demonstrate that SDIA extinction memory destabilization and restabilization necessitate hippocampal NMDARs activation and indicate that GluN2B- and GluN2A-containing NMDAR
Summary
Recall reactivates memories that lay dormant and may affect their strength and endurance. When triggered by a single brief re-presentation of the conditioned stimulus in the absence of the unconditioned stimulus, recall can destabilize well-consolidated memories, which must undergo protein synthesis-dependent reconsolidation to persist. Repetitive non-reinforced recall events may induce extinction, a protein synthesis-dependent process that generates a new memory that prevents the original one from continuing to control behavior. In the case of fear-motivated avoidance, the reconsolidation of extinction memory requires mTOR-dependent BDNF expression in the dorsal h ippocampus[3,4], but the upstream pathways controlling this process remain largely unknown. Of the intra-dorsal CA1 administration of non-subunit specific and subunit-specific NMDAR antagonists at different time points around the moment of step-down inhibitory avoidance (SDIA) extinction memory recall
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