Involvement of different signaling pathways in mouse hippocampus in the modulatory effects of rottlerin and MK-801 on inhibitory avoidance memory

Abstract

Post-traumatic stress disorder (PTSD) is the psychopathological outcome of a traumatic event exposure. However, the current pharmalogical treatments are not effective. Rottlerin and MK-801 have previously been shown to possess antidepressive effects. The eEF2K, which phosphorylates eukaryotic elongation factor 2 (eEF2), is one of the downstream signaling molecules of the N-methyl-D-aspartic acid receptor (NMDAR). Rottlerin inhibits eukaryotic elongation factor 2 kinase (eEF2K), hence increases the levels of brain-derived neurotrophic factor (BDNF) protein in the hippocampus. Likewise, MK-801, a non-competitive antagonist of NMDAR, exerts a fast-acting antidepressive effect through the eEF2K inhibition-mediated increase of BDNF protein in the hippocampus. Furthermore, the NMDA receptors in the dorsal hippocampus are involved in the establishment of long-term memory of the inhibitory avoidance task. The inhibitory avoidance task is widely used in the preclinical research to assess aversive memory and avoidance behavior, which is one of the symptom clusters in the PTSD. Therefore, the present study aimed to investigate the modulatory effects of rottlerin and MK-801 on inhibitory avoidance memory. We first showed that systemic rottlerin impaired memory acquisition, consolidation and retrieval of the inhibitory avoidance memory, whereas had no effect on memory reconsolidation. Systemic MK-801 impaired acquisition of the same aversive memory, which was confounded by MK-801-induced increase of shock sensitivity. Intriguingly, MK-801 (0.25 mg/kg) facilitated memory consolidation and retrieval of the inhibitory avoidance memory without affecting memory reconsolidation. Moreover, the intra-hippocampal infusion of rottlerin significantly impaired memory acquisition, consolidation and retrieval of aversive memory, which was accompanied by decrease of eEF2 and increase of BDNF protein levels in the hippocampus. On the other hand, the intra-hippocampal infusion of MK-801 significantly faciliated memory acquisition, consolidation and retrieval of aversive memory. The memory facilitating effect of MK-801 is correlated with the increase of mTOR protein phosphorylation without changing BDNF levels in the hippocampus. Rottlerin and MK-801 may affected distinct signaling pathways that produced the opposite effects on IA memory consolidation.Taken together, despite having similar antidepressive function, rottlerin and MK-801 display oppositive effects on inhibitory avoidance memory, which are mediated by different signaling pathways in mouse hippocampus. Rottlerin may be a remedy for PTSD via increase of BDNF protein in the hippocampus. By contrast, MK-801 may enhance aversive memory, hence worsen PTSD symptoms through activating hippocampal mTOR signaling pathways. Our results suggest that hippocampal BDNF and mTOR signaling pathways may serve as a potential therapeutic target for PTSD.

Date of Award	2018 Aug
Original language	English
Supervisor	Shu-Jung Hu (Supervisor)