Administration of a Histone Deacetylase Inhibitor into the Basolateral Amygdala Enhances Memory Consolidation, Delays Extinction, and Increases Hippocampal BDNF Levels.

Gene expression related to the formation and modification of memories is regulated epigenetically by chromatin remodeling through histone acetylation. Memory formation and extinction can be enhanced by treatment with inhibitors of histone deacetylases (HDACs). The basolateral amygdala (BLA) is a brain area critically involved in regulating memory for inhibitory avoidance (IA). However, previous studies have not examined the effects of HDAC inhibition in the amygdala on memory for IA. Here we show that infusion of an HDAC inhibitor (HDACi), trichostatin A (TSA), into the BLA, enhanced consolidation of IA memory in rats when given at 1.5, 3, or 6 h posttraining, but not when the drug was infused immediately after training. In addition, intra-BLA administration of TSA immediately after retrieval delayed extinction learning. Moreover, we show that intra-BLA TSA in rats given IA training increased the levels of brain-derived neurotrophic factor in the dorsal hippocampus, but not in the BLA itself. These findings reveal novel aspects of the regulation of fear memory by epigenetic mechanisms in the amygdala.

Histone deacetylase inhibition prevents the impairing effects of hippocampal gastrin-releasing peptide receptor antagonism on memory consolidation and extinction.

Hippocampal gastrin-releasing peptide receptors (GRPR) regulate memory formation and extinction, and disturbances in GRPR signaling may contribute to cognitive impairment associated with neurodevelopmental disorders. Histone acetylation is an important epigenetic mechanism that regulates gene expression involved in memory formation, and histone deacetylase inhibitors (HDACis) rescue memory deficits in several models. The present study determined whether inhibiting histone deacetylation would prevent memory impairments produced by GRPR blockade in the hippocampus. Male Wistar rats were given an intrahippocampal infusion of saline (SAL) or the HDACi sodium butyrate (NaB) shortly before inhibitory avoidance (IA) training, followed by an infusion of either SAL or the selective GRPR antagonist RC-3095 immediately after training. In a second experiment, the infusions were administered before and after a retention test trial that served as extinction training. As expected, RC-3095 significantly impaired consolidation and extinction of IA memory. More importantly, pretraining administration of NaB, at a dose that had no effect when given alone, prevented the effects of RC-3095. In addition, the combination of NaB and RC-3095 increased hippocampal levels of the brain-derived neurotrophic factor (BDNF). These findings indicate that HDAC inhibition can protect against memory impairment caused by GRPR blockade.

TrkB blockade in the hippocampus after training or retrieval impairs memory: protection from consolidation impairment by histone deacetylase inhibition.

Relatively little is known about the requirement of signaling initiated by brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin receptor kinase B (TrkB), in the early phases of memory consolidation, as well as about its possible functional interactions with epigenetic mechanisms. Here we show that blocking TrkB in the dorsal hippocampus after learning or retrieval impairs retention of memory for inhibitory avoidance (IA). More importantly, the impairing effect of TrkB antagonism on consolidation was completely prevented by the histone deacetylase (HDAC) inhibitor sodium butyrate (NaB). Male Wistar rats were given an intrahippocampal infusion of saline (SAL) or NaB before training, followed by an infusion of either vehicle (VEH) or the selective TrkB antagonist ANA-12 immediately after training. In a second experiment, the infusions were administered before and after retrieval. ANA-12 after either training or retrieval produced a significant impairment in a subsequent memory retention test. Pretraining administration of NaB prevented the effect of ANA-12, although NaB given before retrieval did not alter the impairment resulting from TrkB blockade. The results indicate that inhibition of BDNF/TrkB in the hippocampus can hinder consolidation and reconsolidation of IA memory. However, TrkB activity is not required for consolidation in the presence of NaB, suggesting that a dysfunction in BDNF/TrkB signaling can be fully compensated by HDAC inhibition to allow hippocampal memory formation.

Two waves of proteasome-dependent protein degradation in the hippocampus are required for recognition memory consolidation.

Healthy neuronal function and synaptic modification require a concert of synthesis and degradation of proteins. Increasing evidence indicates that protein turnover mediated by proteasome activity is involved in long-term synaptic plasticity and memory. However, its role in different phases of memory remains debated, and previous studies have not examined the possible requirement of protein degradation in recognition memory. Here, we show that the proteasome inhibitor, lactacystin (LAC), infused into the CA1 area of the hippocampus at two specific time points during consolidation, impairs 24-retention of memory for object recognition in rats. Administration of LAC after retrieval did not affect retention. These findings provide the first evidence for a requirement of proteasome activity in recognition memory, indicate that protein degradation in the hippocampus is necessary during selective time windows of memory consolidation, and further our understanding of the role of protein turnover in memory formation.