PARP-1 activity is required for the reconsolidation and extinction of contextual fear memory.

BACKGROUND: Memory consolidation, reconsolidation, and extinction have been shown to require new gene expression. Poly ADP-ribosylation mediated by poly (ADP-ribose) polymerase-1 (PARP-1) is known to regulate transcription through histone modification. Recent studies have suggested that PARP-1 positively regulates the formation of long-term memory (LTM); however, the roles of PARP-1 in memory processes, especially processes after retrieval, remain unknown. RESULTS: Here, we show critical roles for PARP-1 in the consolidation, reconsolidation, and extinction of contextual fear memory in mice. We examined the effects of pharmacological inhibition of PARP-1 activity in the hippocampus or medial prefrontal cortex (mPFC) on these memory processes. Similarly with previous findings, a micro-infusion of the PARP-1 inhibitor 3-aminobenzamide or PJ34 into the dorsal hippocampus, but not mPFC, impaired LTM formation without affecting short-term memory (STM). Importantly, this pharmacological blockade of PARP-1 in the dorsal hippocampus, but not mPFC, also disrupted post-reactivation LTM without affecting post-reactivation STM. Conversely, micro-infusion of the PARP-1 inhibitors into the mPFC, but not dorsal hippocampus, blocked long-term extinction. Additionally, systemic administration of the PARP-1 inhibitor Tiq-A blocked c-fos induction in the hippocampus, which is observed when memory is consolidated or reconsolidated, and also blocked c-fos induction in the mPFC, which is observed when memory is extinguished. CONCLUSIONS: Our observations showed that PARP-1 activation is required for the consolidation, reconsolidation, and extinction of contextual fear memory and suggested that PARP-1 contributes to the new gene expression necessary for these memory processes.

Activation of LVGCCs and CB1 receptors required for destabilization of reactivated contextual fear memories.

Previous studies have shown that inhibiting protein synthesis shortly after reactivation impairs the subsequent expression of a previously consolidated fear memory. This has suggested that reactivation returns a memory to a labile state and that protein synthesis is required for the subsequent restabilization of memory. While the molecular mechanisms underlying the restabilization of reactivated memories are being uncovered, those underlying the initial destabilization are not known at all. Using a contextual fear conditioning paradigm in mice, here we show that LVGCCs or CB1 receptors in hippocampus are required for the initial destabilization of reactivated memory. Either pharmacological blockade of hippocampal protein synthesis or genetic disruption of CREB-dependent transcription disrupts memory restabilization following reactivation. However, these effects were completely blocked when mice were treated with inhibitors of either LVGCCs or CB1 receptors, indicating that LVGCCs or CB1 receptors are required for the initial destabilization of reactivated memory. In control experiments, we show that blockade of LVGCCs or CB1 receptors does not interfere with the ability of ANI to block protein synthesis, or with the ability of ANI to impair initial consolidation. These experiments begin to reveal mechanisms underlying the destabilization of previously consolidated memories following reactivation and indicate the importance of activation of LVGCCs and CB1 in this process.