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Contribution of Hippocampal 5-HT3 Receptors in Hippocampal Autophagy and Extinction of Conditioned Fear Responses after a Single Prolonged Stress Exposure in Rats

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Abstract

One of the hypotheses about the pathogenesis of posttraumatic stress disorder (PTSD) is the dysfunction of serotonin (5-HT) neurotransmission. While certain 5-HT receptor subtypes are likely critical for the symptoms of PTSD, few studies have examined the role of 5-HT3 receptor in the development of PTSD, even though 5-HT3 receptor is critical for contextual fear extinction and anxiety-like behavior. Therefore, we hypothesized that stimulation of 5-HT3 receptor in the dorsal hippocampus (DH) could prevent hippocampal autophagy and the development of PTSD-like behavior in animals. To this end, we infused SR57227, selective 5-HT3 agonist, into the DH after a single prolonged stress (SPS) treatment in rats. Three weeks later, we evaluated the effects of this pharmacological treatment on anxiety-related behaviors and extinction of contextual fear memory. We also accessed hippocampal autophagy and the expression of 5-HT3A subunit, Beclin-1, LC3-I, and LC3-II in the DH. We found that SPS treatment did not alter anxiety-related behaviors but prolonged the extinction of contextual fear memory, and such a behavioral phenomenon was correlated with increased hippocampal autophagy, decreased 5-HT3A expression, and increased expression of Beclin-1 and LC3-II/LC3-I ratio in the DH. Furthermore, intraDH infusions of SR57227 dose-dependently promoted the extinction of contextual fear memory, prevented hippocampal autophagy, and decreased expression of Beclin-1 and LC3-II/LC3-I ratio in the DH. These results indicated that 5-HT3 receptor in the hippocampus may play a critical role in the pathogenesis of hippocampal autophagy, and is likely involved in the pathophysiology of PTSD.

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Acknowledgments

We thank Professor Marong Fang for his valuable suggestions on this paper.

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This work was supported by Zhejiang Provincial Science and Technology Department of Public Welfare Technology Application Project (2014C37026).

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  1. Department of Anatomy, Medical College of Taizhou University, 1139 Taizhou city government Avenue, Taizhou, 318000, China

    Zhong-Min Wu & Yong Liang

  2. Department of Neurology, Taizhou Hospital, Taizhou, 317000, China

    Li-Hua Yang

  3. Department of Neurology, First People’s Hospital of Linhai City, Linhai, 317000, China

    Zhong-Min Wu, Rong Cui & Gui-Lian Ni

  4. City College of Zhejiang University, Hangzhou, 310015, China

    Feng-Tian Wu

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  1. Zhong-Min Wu
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Wu, ZM., Yang, LH., Cui, R. et al. Contribution of Hippocampal 5-HT3 Receptors in Hippocampal Autophagy and Extinction of Conditioned Fear Responses after a Single Prolonged Stress Exposure in Rats. Cell Mol Neurobiol 37, 595–606 (2017). https://doi.org/10.1007/s10571-016-0395-7

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