Vincent Martin, PharmD, PhD; Lionel Mathieu, MD; Jorge Diaz, PhD; Haysam Salman, MSc; Jeanine Alterio, PhD; Caroline Chevarin, MSc; Laurence Lanfumey, PhD; Michel Hamon, PhD; Mark C. Austin, PhD; Michèle Darmon, PhD; Craig A. Stockmeier, PhD; Justine Masson, PhD
Background: Altered function of serotonin receptor 1A (5-HT1AR) has been consistently implicated in anxiety, major depressive disorder and resistance to antidepressants. Mechanisms by which the function of 5-HT1AR (expressed as an autoreceptor in serotonergic raphe neurons and as a heteroreceptor in serotonin [5-HT] projection areas) is altered include regulation of its expression, but 5-HT1AR trafficking may also be involved.
Methods: We investigated the consequences of the lack of Yif1B (the 5-HT1AR trafficking protein) on 5-HT neurotransmission in mice, and whether Yif1B expression might be affected under conditions known to alter 5-HT neurotransmission, such as anxious or depressive states or following treatment with fluoxetine (a selective serotonin reuptake inhibitor) in humans, monkeys and mice.
Results: Compared with wild-type mice, Yif1B-knockout mice showed a significant decrease in the forebrain density of 5-HT projection fibres and a hypofunctionality of 5-HT1A autoreceptors expressed on raphe 5-HT neurons. In addition, social interaction was less in Yif1B-knockout mice, which did not respond to the antidepressant-like effect of acute fluoxetine injection. In wild-type mice, social defeat was associated with downregulated Yif1B mRNA in the prefrontal cortex, and chronic fluoxetine treatment increased Yif1B expression. The expression of Yif1B was also downregulated in the postmortem prefrontal cortex of people with major depressive disorder and upregulated after chronic treatment with a selective serotonin reuptake inhibitor in monkeys.
Limitations: We found sex differences in Yif1B expression in humans and monkeys, but not in mice under the tested conditions.
Conclusion: These data support the concept that Yif1B plays a critical role in 5-HT1AR functioning and brain 5-HT homeostasis. The opposite changes in its expression observed in anxious or depressive states and after therapeutic fluoxetine treatment suggest that Yif1B might be involved in vulnerability to anxiety and depression, and fluoxetine efficacy.
Submitted Jul. 22, 2019; Revised Oct. 17, 2019; Accepted Nov. 5, 2019; Published online May 27, 2020
Acknowledgments: The authors are grateful to Elodie Stievenard for technical help, Gwenaëlle Le Pen for performing statistical analyses, and Sana Al Awabdh and Jean-Antoine Girault for advice on the manuscript editing. We are grateful for the assistance of the next of kin of the deceased and acknowledge the excellent assistance of the Cuyahoga County Medical Examiner’s Office, Cleveland, Ohio. We thank the NAC staff for technical assistance and animal care.
Affiliations: From Inserm UMR894, Centre de Psychiatrie et Neuroscience, Paris F-75014 France; Université Paris Descartes, Sorbonne Paris Cité – Paris 5, France (Martin, Mathieu, Diaz, Salman, Alterio, Chevarin, Lanfumey, Hamon, Darmon, Masson); the College of Pharmacy, Idaho State University, Pocatello, ID 83209 USA (Austin); the Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, MS, 39216 USA (Stockmeier); and Inserm UMR-S 1270, Paris, France; Sorbonne Université, Science and Engineering Faculty, Paris, France; Institut du Fer à Moulin, Paris, France (Darmon, Masson).
Funding: This work was supported by Inserm, University Paris Descartes, and the Postmortem Brain Core and Animal Behavior Core funded by the National Institutes of Health COBRE grant P30GM103328. J. Masson is supported by Centre National de la Recherche Scientifique and J. Alterio by Paris 12 University.
Competing interests: None declared.
Contributors: M. Hamon, M. Austin and J. Masson designed the study. V. Martin, L. Mathieu, J. Diaz, H. Salman, J. Alterio, C. Chevarin, M. Austin, M. Darmon and J. Masson acquired the data, which V. Martin, L. Mathieu, J. Diaz, J. Alterio, L. Lanfumey, M. Darmon, C. Stockmeier and J. Masson analyzed. V. Martin, L. Mathieu, H. Salman, M. Austin and J. Masson wrote the article, which all authors reviewed. All authors approved the final version to be published and can certify that no other individuals not listed as authors have made substantial contributions to the paper.
Correspondence to: J. Masson, Inserm, UMR-S 1270, Institut du Fer à Moulin, 17 Rue du Fer à Moulin, 75005 Paris, France; firstname.lastname@example.org