title: SiRNA-mediated serotonin transporter knockdown in the dorsal raphe nucleus rescues single prolonged stress-induced hippocampal autophagy in rats.
abstract: The neurobiological mechanisms underlying the development of post-traumatic stress disorder (PTSD) remain elusive. One of the hypotheses is the dysfunction of serotonin (5-HT) neurotransmission, which is critically regulated by serotonin transporter (SERT). Therefore, we hypothesized that attenuation of SERT gene expression in the hippocampus could prevent hippocampal autophagy and the development of PTSD-like behavior. To this end, we infused SLC6A4 siRNAs into the dorsal raphe nucleus (DRN) to knockdown SERT gene expression after a single prolonged stress (SPS) treatment in rats. Then, we evaluated the effects of SERT gene knockdown on anxiety-related behaviors and extinction of contextual fear memory. We also examined the histological changes and the expression of Beclin-1, LC3-I, and LC3-II in the hippocampus. 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-HT level, and increased expression of Beclin-1 and LC3-II/LC3-I ratio in the hippocampus. Furthermore, intra-DRN infusion of SLC6A4 siRNAs promoted the extinction of contextual fear memory, prevented hippocampal autophagy, increased 5-HT level, and decreased expression of Beclin-1 and LC3-II/LC3-I ratio. These results indicated that SERT may play a critical role in the pathogenesis of hippocampal autophagy, and is likely involved in the development of PTSD.
authors.affiliation: Department of anatomy, Medical College of Taizhou University, Taizhou 318000, China; Department of Neurology, First People's Hospital of Linhai City, Linhai 317000, China.
authors.forename: Zhong-Min
authors.initials: ZM
authors.lastname: Wu
authors.affiliation: Outpatient Office, Taizhou Hospital, Taizhou 317000, China.
authors.forename: Chun-Hua
authors.initials: CH
authors.lastname: Zheng
authors.affiliation: Department of Pediatrics, Taizhou Central Hospital, Taizhou 318000, China.
authors.forename: Zhen-Hua
authors.initials: ZH
authors.lastname: Zhu
authors.affiliation: City Colloege of Zhejiang University, Hanzhou 310031, China.
authors.forename: Feng-Tian
authors.initials: FT
authors.lastname: Wu
authors.affiliation: Department of Neurology, First People's Hospital of Linhai City, Linhai 317000, China.
authors.forename: Gui-Lian
authors.initials: GL
authors.lastname: Ni
authors.affiliation: Department of anatomy, Medical College of Taizhou University, Taizhou 318000, China. Electronic address: yonggliang@sina.com.
authors.forename: Yong
authors.initials: Y
authors.lastname: Liang
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D001343:Autophagy / Q000502:physiology*; D000071186:Beclin-1; D001522:Behavior, Animal / Q000502:physiology; D065847:Dorsal Raphe Nucleus / Q000378:metabolism*; D005108:Extinction, Psychological / Q000502:physiology; D005239:Fear / Q000502:physiology; D006624:Hippocampus / Q000378:metabolism*; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering; D051381:Rats; D017207:Rats, Sprague-Dawley; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism; D013315:Stress, Psychological / Q000235:genetics* / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; D008869:Microtubule-Associated Proteins; D034741:RNA, Small Interfering; D050486:Serotonin Plasma Membrane Transport Proteins; C512829:Becn1 protein, rat; C526109:Anxa3 protein, rat
keywords: Dorsal raphe nucleus; Hippocampal autophagy; Post-traumatic stress disorder; Serotonin transporter; Small interfering RNA