Contribution of Hippocampal 5-HT3 Receptors in Hippocampal Autophagy and Extinction of Conditioned Fear Responses after a Single Prolonged Stress Exposure in Rats
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.
Keywords5-HT3 receptor Hippocampal autophagy Posttraumatic stress disorder Conditioned fear response Memory extinction
We thank Professor Marong Fang for his valuable suggestions on this paper.
This work was supported by Zhejiang Provincial Science and Technology Department of Public Welfare Technology Application Project (2014C37026).
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflict of interest.
All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.
- Banasr M, Hery M, Printemps R, Daszuta A (2004) Serotonin-induced increases in adult cell proliferation and neurogenesis are mediated through different and common 5-HT receptor subtypes in the dentate gyrus and the subventricular zone. Neuropsychopharmacology 29(3):450–460. doi: 10.1038/sj.npp.1300320 CrossRefPubMedGoogle Scholar
- Castilla-Ortega E, Hoyo-Becerra C, Pedraza C, Chun J, Rodriguez De Fonseca F, Estivill-Torrus G, Santin LJ (2011) Aggravation of chronic stress effects on hippocampal neurogenesis and spatial memory in LPA(1) receptor knockout mice. PLoS ONE 6(9):e25522. doi: 10.1371/journal.pone.0025522 CrossRefPubMedPubMedCentralGoogle Scholar
- Hoskins M, Pearce J, Bethell A, Dankova L, Barbui C, Tol WA, van Ommeren M, de Jong J, Seedat S, Chen H, Bisson JI (2015) Pharmacotherapy for post-traumatic stress disorder: systematic review and meta-analysis. Br J Psychiatry 206(2):93–100. doi: 10.1192/bjp.bp.114.148551 CrossRefPubMedGoogle Scholar
- Koike M, Shibata M, Tadakoshi M, Gotoh K, Komatsu M, Waguri S, Kawahara N, Kuida K, Nagata S, Kominami E, Tanaka K, Uchiyama Y (2008) Inhibition of autophagy prevents hippocampal pyramidal neuron death after hypoxic-ischemic injury. Am J Pathol 172(2):454–469. doi: 10.2353/ajpath.2008.070876 CrossRefPubMedPubMedCentralGoogle Scholar
- Murrough JW, Czermak C, Henry S, Nabulsi N, Gallezot JD, Gueorguieva R, Planeta-Wilson B, Krystal JH, Neumaier JF, Huang Y, Ding YS, Carson RE, Neumeister A (2011) The effect of early trauma exposure on serotonin type 1B receptor expression revealed by reduced selective radioligand binding. Arch Gen Psychiatry 68(9):892–900. doi: 10.1001/archgenpsychiatry.2011.91 CrossRefPubMedPubMedCentralGoogle Scholar