GABAA Receptor Blockade Enhances Memory Consolidation by Increasing Hippocampal BDNF Levels

Abstract

Memory consolidation is the process by which acquired information is converted to something concrete to be retrieved later. Here we examined a potential role for brain-derived neurotrophic factor (BDNF) in mediating the enhanced memory consolidation induced by the GABA(A) receptor antagonist, bicuculline methiodide. With the administration of an acquisition trial in naïve mice using a passive avoidance task, mature BDNF (mBDNF) levels were temporally changed in the hippocampal CA1 region, and the lowest levels were observed 9 h after the acquisition trial. In the passive avoidance task, bicuculline methiodide administration within 1 h of training but not after 3 h significantly increased latency time in the retention trial 24 h after the acquisition trial. Concomitantly, 1 h post-training administration of bicuculline methiodide, which enhanced memory consolidation, significantly increased mBDNF levels 9 h after training compared to those of the vehicle-treated control group. In addition, exogenous human recombinant BDNF (hrBDNF) administration 9 h after training into the hippocampal CA1 region facilitated memory consolidation confirming that the increase in mBDNF at around 9 h after training plays a key role in the enhancement of memory consolidation. Moreover, the increases in latency time and immediate early gene expressions by bicuculline methiodide or hrBDNF were significantly blocked by anisomycin, a protein synthesis inhibitor, K252a, a tyrosine receptor kinase (Trk) inhibitor, or anti-TrkB IgG. These findings suggest that the increase in the level of mBDNF and its function during a restricted time window after training are required for the enhancement of memory consolidation by GABA(A) receptor blockade.

Exercise combined with low-level GABAA receptor inhibition up-regulates the expression of neurotrophins in the motor cortex

“…Similar results were reported by Yousefi et al [9]. Kim et al reported that bicuculline methiodide administration into the hippocampus or prefrontal cortex enhanced memory consolidation by increasing hippocampal BDNF expression [6]. In addition, GABAA receptor antagonists are reported to induce long term potentiation (LTP) in hippocampal neurons [18] and up-regulate BDNF mRNA expression in hypothalamic neurons [19] in vitro.…”

“…As abovementioned, several studies have indicated that exercise acutely increases the expression of BDNF in a manner that peaks 2-3 h after exercise and gradually decreases to baseline 24 h after exercise [12,16]. On the contrary, previous literatures show that protein expression starts to increase after 6 h after exercise and 9 h after GABAA receptor inhibition by bicuculline methioide administration [6,26]. In addition, mice sleep longer and more deeply after exercise [27]; acute over-excitation induced by bicuculline administration might potentiate this exercise-induced behavioral modification, i.e.…”

Exogenous insulin-like growth factor 2 administration enhances memory consolidation and persistence in a time-dependent manner

“…For example, the treatment of anisomycin or cycloheximide, a protein synthesis inhibitor, into the hippocampus 3-6 h after the training impaired the formation of LTM. However, at 9-12 h post-training, a protein synthesis inhibitor had no effect on memory formation (Bekinschtein et al, 2007;Kim et al, 2012). Additionally, it was reported that hippocampal mBDNF expression levels in the hippocampus 9 h after the acquisition trial is critically involved in the enhancement of memory consolidation (Kim et al, 2012(Kim et al, , 2014Kwon et al, 2014).…”

“…It has previously been reported that the inhibition of de novo protein synthesis with anisomysin or cycloheximide in the hippocampus approximately 3-6 h after the initial acquisition impaired memory consolidation, whereas it did not induce impairments 12 h after the acquisition trial (Bekinschtein et al, 2007;Kim et al, 2012). We recently reported that mature brain-derived neurotrophic factor (mBDNF) in the hippocampus enhances memory consolidation within 9 h after initial learning (Kim et al, 2012(Kim et al, , 2014Kwon et al, 2014). Furthermore, several lines of evidence have demonstrated that a late consolidation phase, approximately 12 h after initial learning, is required for the persistence of LTM.…”

A BDNF sensitive mechanism is involved in the fear memory resulting from the interaction between stress and the retrieval of an established trace

“…It was proposed that the reduction of this inhibitory mechanism in BLA enhanced activation of downstream structures implicated in generating a robust emotional response and leading to excessive emotional output to mild aversive stimulation or to stimulus that would normally induce minimal emotional disturbance (Martijena et al 2002;Calfa et al 2006;Bignante et al 2008). What is more, stress and pharmacologically induced decrease of GABAergic neurotransmission, particularly in BLA, enhance the emergence of fear memory (Rodriguez Manzanares et al 2005;Kim et al 2012). A logical prediction from all this evidence suggests that the activation of GABAa sites in BLA prior to the environmental challenge would prevent the enhancing effect on the expression and retention of fear following the interaction of stress and recall.…”