title: Enhanced 5-HT1A receptor-dependent feedback control over dorsal raphe serotonin neurons in the SERT knockout mouse.
abstract: 5-HT1A receptors are widely expressed in the brain and play a critical role in feedback inhibition of serotonin (5-HT) neurons through multiple mechanisms. Yet, it remains poorly understood how these feedback mechanisms, particularly those involving long-range projections, adapt in mood disorders. Here, we examined several aspects of 5-HT1A receptor function in the 5-HT transporter knockout mouse (SERT-KO), a model of vulnerability to stress and mood disorders. We found that in comparison to wild-type (WT) mice, SERT-KO mice had more passive coping in response to acute swim stress and this was accompanied by hypo-activation of medial prefrontal cortex (mPFC) Fos expression. Both of these effects were reversed by systemically blocking 5-HT1A receptors. Ex-vivo electrophysiological experiments showed that 5-HT exerted greater 5-HT1A-mediated inhibitory effects in the mPFC of SERT-KO mice compared to WT. Since 5-HT1A receptors in the mPFC provide a key feedback regulation of the dorsal raphe nucleus (DRN), we used a disinhibition strategy to examined endogenous feedback control of 5-HT neurons. Blocking 5-HT1A receptors disinhibited several fold more 5-HT neurons in the DRN of SERT-KO than in WT mice, revealing the presence of enhanced feedback inhibition of 5-HT neurons in the SERT-KO. Taken together our results indicate that increased stress sensitivity in the SERT-KO is associated with the enhanced capacity of 5-HT1A receptors to inhibit neurons in the mPFC as well as to exert feedback inhibition of DRN 5-HT neurons.
authors.affiliation: Department of Anesthesiology, Perioperative, and Pain Medicine, Boston Children's Hospital, 300 Longwood Ave., Boston, MA 02115, USA; Department of Anaesthesia, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Mariano
authors.initials: M
authors.lastname: Soiza-Reilly
authors.affiliation: Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Nathalie M
authors.initials: NM
authors.lastname: Goodfellow
authors.affiliation: Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Obstetrics and Gynaecology, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Evelyn K
authors.initials: EK
authors.lastname: Lambe
authors.affiliation: Department of Anesthesiology, Perioperative, and Pain Medicine, Boston Children's Hospital, 300 Longwood Ave., Boston, MA 02115, USA; Department of Anaesthesia, Harvard Medical School, Boston, MA 02115, USA. Electronic address: kathryn.commons@childrens.harvard.edu.
authors.forename: Kathryn G
authors.initials: KG
authors.lastname: Commons
mesh_terms: D000818:Animals; D065847:Dorsal Raphe Nucleus / Q000187:drug effects / Q000378:metabolism*; D025461:Feedback, Physiological / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D044282:Receptor, Serotonin, 5-HT1A / Q000502:physiology*; D058829:Serotonin 5-HT1 Receptor Antagonists / Q000494:pharmacology; D050486:Serotonin Plasma Membrane Transport Proteins / Q000172:deficiency*
chemical_list: D058829:Serotonin 5-HT1 Receptor Antagonists; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; D044282:Receptor, Serotonin, 5-HT1A
keywords: Depressive-like behavior; Dorsal raphe nucleus; Feedback inhibition; Mood disorders; Serotonin transporter; Swim stress