Rottlerin, BDNF, and the impairment of inhibitory avoidance memory.

RATIONALE AND OBJECTIVE: As a eukaryotic elongation factor 2 kinase (eEF2K) inhibitor and a mitochondrial uncoupler, oncologists have extensively studied rottlerin. Neuroscientists, however, have accumulated scarce data on the role of rottlerin in affective and cognitive functions. Only two prior studies have, respectively, documented its antidepressant-like effect and how it impairs psychostimulant-supported memory. Whether or not rottlerin would affect aversive memory remains unknown. Hence, we sought to investigate the effects of rottlerin on aversive memory in the inhibitory avoidance (IA) task in mice. MATERIALS AND METHODS: Male C57BL/6J mice were trained to acquire the IA task. Rottlerin (5 mg/kg, i.p. or 3 µg bilaterally in the hippocampus) or the vehicle was administered before footshock training (acquisition), after footshock training (consolidation), after the memory reactivation (reconsolidation), and before the test (retrieval) in the IA task. RESULTS: Systemic and intrahippocampal rottlerin impaired the acquisition, consolidation, and retrieval of IA memory, without affecting the reconsolidation process. Rottlerin (5 mg/kg, i.p.) induced a fast-onset and long-lasting increase in the brain-derived neurotrophic factor (BDNF) protein levels in the mouse hippocampus. Systemic injection of 7,8-dihydroxyflavone (7,8-DHF, 30 mg/kg), a BDNF tropomyosin receptor kinase B (TrkB) agonist impaired IA memory consolidation, and treatment with K252a (5 µg/kg), a Trk receptor antagonist, reversed the suppressing effect of rottlerin on IA memory consolidation. CONCLUSION: Rottlerin impairs IA memory consolidation through the enhancement of BDNF signaling in the mouse hippocampus. Excessive brain BDNF levels can be detrimental to cognitive function. Rottlerin is likely to affect the original memory-associated neuroplasticity. Thus, it can be combined with exposure therapy to facilitate the forgetting of maladaptive aversive memory, such as post-traumatic stress disorder (PTSD).

The facilitating effect of MK-801 on inhibitory avoidance memory via mTOR signaling in the mouse hippocampus.

Despite the widespread belief that MK-801 induces memory deficits associated with dementia and schizophrenia in animal models, data regarding the impairing effect of MK-801 on aversive memory have been inconclusive. In this study, we investigated the effect of MK-801 on multiple memory stages of the inhibitory avoidance task, as well as its underlying signaling mechanism in the mouse hippocampus. We successfully replicated a previous finding suggesting that systemic injection of MK-801 impaired memory acquisition, but we observed that an intrahippocampal infusion of MK-801 facilitated the same memory process. We also found that both systemic and intrahippocampal administration of MK-801 facilitated memory consolidation and memory retrieval of the inhibitory avoidance task. We demonstrated that MK-801-induced increases in shock sensitivity and locomotor activity in the pre-training regimen confounded the detrimental effect of MK-801 on memory acquisition, thereby reconciling the inconsistent results in previous studies. In addition, the memory-facilitating effect of MK-801 was found to be dependent on drug dose and shock intensity. We next showed that MK-801 induced a fast-onset increase in the extent of mammalian target of rapamycin (mTOR) phosphorylation in the hippocampus. Finally, we observed that rapamycin, an mTOR inhibitor, blocked both the MK-801-induced increases in phosphorylated mTOR and the facilitating effect of MK-801 on memory consolidation. These results indicate that hippocampal mTOR signaling mediates the facilitating effect of MK-801 on memory consolidation of the inhibitory avoidance task. These findings further imply that MK-801 indeed functions as a memory enhancer and that mTOR signaling serves as a therapeutic target for memory disorders.