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Rottlerin, BDNF, and the impairment of inhibitory avoidance memory

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Abstract

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).

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Abbreviations

IA:

Inhibitory avoidance

BDNF:

Brain-derived neurotrophic factor

eEF2K:

Eukaryotic elongation factor 2 kinase

mTOR:

Mammalian target of rapamycin

PKC:

Protein kinase C

TrkB:

Tropomyosin receptor kinase B

7,8-DHF:

7,8-Dihydroxyflavone

DMSO:

Dimethyl sulfoxide

PTSD:

Post-traumatic stress disorder

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Acknowledgments

We thank Drs. Keng-Chen Liang and Der-Yow Chen for their generous help with the fear-potentiated startle experiment. We thank Li-Yu Kan and all of the Hu lab members for technical assistance.

Funding

This work was supported by the ROC Ministry of Science and Technology (MOST) grant Nos. 104-2410-H-006-025-MY3, 105-2410-H-006-019-MY2, and 107-2410-H-006-056- to SSH.

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  1. Wan-Ling Huang and Ming-Heng Hsiung contributed equally to this work.

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  1. Cannabinoid Signaling Laboratory, Department of Psychology, National Cheng Kung University, 1 University Rd, Tainan, 70101, Taiwan

    Wan-Ling Huang, Ming-Heng Hsiung, Wen Dai & Sherry Shu-Jung Hu

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  1. Wan-Ling Huang
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Contributions

Wan-Ling Huang: project administration, resources, validation, investigation.

Ming-Heng Hsiung: project administration, formal analysis, investigation.

Wen Dai: validation, investigation.

Sherry Shu-Jung Hu: funding acquisition, writing—review and editing, writing—original draft, supervision, conceptualization.

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Correspondence to Sherry Shu-Jung Hu.

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Huang, WL., Hsiung, MH., Dai, W. et al. Rottlerin, BDNF, and the impairment of inhibitory avoidance memory. Psychopharmacology 238, 421–439 (2021). https://doi.org/10.1007/s00213-020-05690-x

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