Ketamine Alleviates Fear Generalization Through GluN2B-BDNF Signaling in Mice

  • Muhammad Asim
  • Bo Hao
  • Yu-Han Yang
  • Bu-Fang Fan
  • Li Xue
  • Yan-Wei ShiEmail author
  • Xiao-Guang WangEmail author
  • Hu Zhao
Original Article


Fear memories are critical for survival. Nevertheless, over-generalization of these memories, depicted by a failure to distinguish threats from safe stimuli, is typical in stress-related disorders. Previous studies have supported a protective role of ketamine against stress-induced depressive behavior. However, the effect of ketamine on fear generalization remains unclear. In this study, we investigated the effects of ketamine on fear generalization in a fear-generalized mouse model. The mice were given a single sub-anesthetic dose of ketamine (30 mg/kg, i.p.) 1 h before, 1 week before, immediately after, or 22 h after fear conditioning. The behavioral measure of fear (indicated by freezing level) and synaptic protein expression in the basolateral amygdala (BLA) and inferior-limbic pre-frontal cortex (IL-PFC) of mice were examined. We found that only ketamine administered 22 h after fear conditioning significantly decreased the fear generalization, and the effect was dose-dependent and lasted for at least 2 weeks. The fear-generalized mice showed a lower level of brain-derived neurotrophic factor (BDNF) and a higher level of GluN2B protein in the BLA and IL-PFC, and this was reversed by a single administration of ketamine. Moreover, the GluN2B antagonist ifenprodil decreased the fear generalization when infused into the IL-PFC, but had no effect when infused into the BLA. Infusion of ANA-12 (an antagonist of the BDNF receptor TrkB) into the BLA or IL-PFC blocked the effect of ketamine on fear generalization. These findings support the conclusion that a single dose of ketamine administered 22 h after fear conditioning alleviates the fear memory generalization in mice and the GluN2B-related BDNF signaling pathway plays an important role in the alleviation of fear generalization.


Ketamine Fear generalization Post-traumatic stress disorder BDNF GluN2B GluN2A 



This work was supported by grants from the National Natural Science Foundation of China (81530061 and 81471829), the Pearl River Nova Program of Guangzhou (201610010154), and the Natural Science Foundation of Guangdong Province China (2017A030313095).

Conflict of interest

All authors claim that there are no conflicts of interest.

Supplementary material

12264_2019_422_MOESM1_ESM.pdf (108 kb)
Supplementary material 1 (PDF 108 kb)


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Copyright information

© Shanghai Institutes for Biological Sciences, CAS 2019

Authors and Affiliations

  • Muhammad Asim
    • 1
    • 2
  • Bo Hao
    • 1
    • 2
  • Yu-Han Yang
    • 1
    • 2
  • Bu-Fang Fan
    • 1
    • 2
  • Li Xue
    • 1
    • 2
    • 3
  • Yan-Wei Shi
    • 1
    • 2
    • 3
    Email author
  • Xiao-Guang Wang
    • 1
    • 2
    • 3
    Email author
  • Hu Zhao
    • 1
    • 2
    • 3
  1. 1.Faculty of Forensic Medicine, Zhongshan School of MedicineSun Yat-sen UniversityGuangzhouChina
  2. 2.Guangdong Province Translational Forensic Medicine Engineering Technology Research Center, Zhongshan School of MedicineSun Yat-sen UniversityGuangzhouChina
  3. 3.Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan School of MedicineSun Yat-sen UniversityGuangzhouChina

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