Fluoxetine Inhibits Natural Decay of Long-Term Memory via Akt/GSK-3β Signaling

  • Jee Hyun Yi
  • JiaBao Zhang
  • Sang Yoon Ko
  • Huiyoung Kwon
  • Se Jin Jeon
  • Se Jin Park
  • Jiwook Jung
  • Byung C. Kim
  • Young Choon Lee
  • Dong Hyun Kim
  • Jong Hoon Ryu


Understanding the mechanisms underlying the natural decay of long-term memory can help us find means of extending the duration of long-term memory. However, the neurobiological processes involved in the decay of long-term memory are poorly understood. In the present study, we examined the effect of acute and chronic treatment of fluoxetine on natural decay of long-term memory and the possible mechanism. Late administration of fluoxetine prolonged the persistence of long-term memory in mice, as demonstrated by object location recognition and Barnes maze tests. Fluoxetine altered Akt/glycogen synthase kinase-3β (GSK-3β)/β-catenin signaling in the hippocampus. Late short- and long-term pharmacological inhibition of GSK-3β mimicked the effect of fluoxetine on memory persistence. Pharmacological inhibition of Akt blocked the effect of fluoxetine on memory persistence. Finally, late infusion of fluoxetine increased hippocampal long-term potentiation (LTP) and pharmacological inhibition of GSK-3β blocked the natural decline in LTP. These results demonstrate that GSK-3β might be a key molecule in memory decay process, and fluoxetine extends the period of long-term memory maintenance via Akt/GSK-3β signaling.


Fluoxetine Memory decay GSK-3β LTP maintenance 



This study was supported by the National Research Foundation of Korea (NRF) grant funded by the Ministry of Education, Science and Technology (MEST) (2017R1C1B1003822, 2016R1A5A2007009, and 2015R1A2A2A01007838).

Compliance with Ethical Standards

The treatment and maintenance of the animals were carried out in accordance with the Animal Care and Use Guidelines Dong-A University and Kyung Hee University, Korea. All of the experimental protocols using animals were approved by the Institutional Animal Care and Use Committee of Dong-A University and Kyung Hee University, Korea.

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

12035_2018_919_MOESM1_ESM.docx (97 kb)
ESM 1 (DOCX 96.9 kb)


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Authors and Affiliations

  1. 1.School of Clinical Sciences, Faculty of Medicine and DentistryUniversity of BristolBristolUK
  2. 2.Department of Oriental Pharmaceutical Science, College of PharmacyKyung Hee UniversitySeoulRepublic of Korea
  3. 3.Department of Medicinal Biotechnology, College of Health SciencesDong-A UniversityBusanRepublic of Korea
  4. 4.School of Natural Resources and Environmental ScienceKangwon National UniversityChuncheonRepublic of Korea
  5. 5.Department of Herbal Medicinal Pharmacology, College of Herbal Bio-industryDaeguHaany UniversityKyungsanRepublic of Korea
  6. 6.Department of NeurologyChonnam National University Medical SchoolGwangjuRepublic of Korea
  7. 7.Institute of Convergence Bio-HealthDong-A UniversityBusanRepublic of Korea
  8. 8.Department of Life and Nanopharmaceutical SciencesKyung Hee UniversitySeoulSouth Korea

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