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Rottlerin, BDNF, and the impairment of inhibitory avoidance memory
Wan-Ling Huang1, Ming-Heng Hsiung1, Wen Dai1
1Cannabinoid Signaling Laboratory, Department of Psychology, National Cheng Kung University, 1 University Rd, Tainan, 70101, Taiwan.
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).
Insights
Rottlerin impairs aversive memory acquisition, consolidation, and retrieval in mice by enhancing brain-derived neurotrophic factor (BDNF) signaling. This suggests potential therapeutic applications for conditions like PTSD.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- Rottlerin is a known eukaryotic elongation factor 2 kinase (eEF2K) inhibitor and mitochondrial uncoupler.
- Limited research exists on rottlerin's effects on cognitive and affective functions.
- Previous studies noted rottlerin's antidepressant-like effect and impairment of psychostimulant-supported memory.
Purpose of the Study:
- To investigate the impact of rottlerin on aversive memory formation and recall.
- To explore rottlerin's effects in the context of the inhibitory avoidance (IA) task in mice.
- To determine if rottlerin influences memory acquisition, consolidation, retrieval, or reconsolidation.
Main Methods:
- Male C57BL/6J mice were trained on the inhibitory avoidance (IA) task.
- Rottlerin was administered systemically (5 mg/kg, i.p.) or intrahippocampally (3 μg) at different memory stages: acquisition, consolidation, reconsolidation, and retrieval.
- Vehicle-treated mice served as controls. BDNF signaling was assessed using 7,8-dihydroxyflavone (7,8-DHF) and K252a.
Main Results:
- Systemic and intrahippocampal rottlerin impaired IA memory acquisition, consolidation, and retrieval.
- Rottlerin did not affect the reconsolidation of IA memory.
- Rottlerin administration increased hippocampal BDNF protein levels; BDNF signaling modulation affected IA memory consolidation.
Conclusions:
- Rottlerin impairs inhibitory avoidance memory consolidation via enhanced hippocampal BDNF signaling.
- Elevated BDNF levels may negatively impact cognitive functions.
- Rottlerin could be a potential adjunct therapy for exposure-based treatments of maladaptive aversive memories, such as in PTSD.
