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

Abstract

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.

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

“…Gene transcription for BDNF is stimulated by HDACis (Wu et al, 2008; Koppel and Timmusk, 2013), and systemic HDACi treatment increases protein levels of BDNF in the rat brain (Kim et al, 2009). In addition, administration of an HDACi into the hippocampus rescues the impairment of IA memory consolidation produced by TrkB inhibition (Blank et al, 2016). …”

“…Administration of HDACis lead to increased acetylation and enhanced gene expression in neurons, resulting in a facilitation of synaptic plasticity as well as formation and extinction of fear conditioning (Levenson et al, 2004; Lattal et al, 2007; Vecsey et al, 2007; Bredy and Barad, 2008; Stafford et al, 2012). Acute systemic or intrahippocampal administration of HDACis enhances IA memory consolidation and rescues IA deficits related to aging or models of memory impairment (Silva et al, 2012; Blank et al, 2014, 2015, 2016; Sharma et al, 2015; Petry et al, 2016). Epigenetic alterations in the lateral amygdala, including increased histone H3 acetylation, are involved in the formation and reconsolidation of memory for auditory fear conditioning in rats.…”

Reconsolidation and extinction: Using epigenetic signatures to challenge conventional wisdom

“…The same group showed that the HDAC inhibitor NaB reversed impairments in memory consolidation (of the original memory) that were due to inhibition of the brain-derived neurotrophic factor (BDNF) tyrosine receptor kinase B (TrkB). However, deficits in memory reconsolidation induced by TrkB inhibition were not reversed by NaB (Blank et al, 2016). A possible explanation for this discrepancy in the finding is that the effect of HDAC inhibition on facilitating memory reconsolidation is restricted to fear conditioning and does not hold for inhibitory avoidance.…”

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

“…1. The general procedures for IA behavioral training and retention tests were described in previous reports [6,7] On training trials, the rats were placed on the platform and their latency to step down on the grid with all four paws was measured with a digital chronometer. Immediately after stepping down on the grid, the rats were given a 0.4-mA, 3.0-s footshock and then removed from the apparatus immediately afterward.…”

“…Rats were implanted under anesthesia with isoflurane (vaporized in 100% oxygen, at a dose of 5% for induction and 2% for maintenance, in a fraction of 0.5 l/min) with bilateral 8-mm, 23-gauge guide cannulae aimed 1.0 mm above the dorsal hippocampus, as described previously [6,7]. Coordinates (anteroposterior, -4.3 mm from bregma; mediolateral, ±3.0 mm from bregma; ventral, -2.0 mm from skull surface) were obtained from the atlas of Paxinos and Watson [38].…”