Microglial production of quinolinic acid as a target and a biomarker of the antidepressant effect of ketamine

Franck Verdonk (1, 2, 3) , Anne-Cécile Petit (1, 4, 5) , Pierre Abdel-Ahad (4, 5, 6) , Fabien Vinckier (4, 5, 6) , Gregory Jouvion (7) , Pierre de Maricourt (4, 5) , Gabriela Ferreira de Medeiros (1) , Anne Danckaert (8, 1) , Juliette van Steenwinckel (9, 10) , Michael Blatzer (1) , Anna Maignan (11) , Olivier Langeron (1, 12) , Tarek Sharshar (1, 5, 13) , Jacques Callebert (14) , Jean-Marie Launay (14) , Fabrice Chrétien (1, 5, 15) , Raphael Gaillard (1, 4, 5)

1 Neuropathologie expérimentale / Experimental neuropathology
2 Service des Soins Intensifs [CHU Saint-Antoine]
3 SU - Sorbonne Université
4 Centre Hospitalier Sainte Anne [Paris]
5 UPD5 - Université Paris Descartes - Paris 5
6 NPS-07 - Physiopathologie des maladies psychiatriques = Pathophysiology of Psychiatric Disorders
7 Histopathologie humaine et Modèles animaux
8 UTechS PBI - BioImagerie Photonique – Photonic BioImaging
9 INSERM - Institut National de la Santé et de la Recherche Médicale
10 UPD7 UFR LAC - Paris Diderot - Paris 7 - UFR Lettres, Arts, Langues
11 Service universitaire de psychiatrie d'adultes
12 Service d'Anesthésie réanimation [CHU Pitié-Salpêtrière]
13 GHU Paris psychiatrie & neurosciences - Neuro-anesthésiologie et Médecine des soins intensifs [CH Sainte-Anne]
14 Service de biochimie et biologie moléculaire
15 Laboratoire Hospitalo-Universitaire de Neuropathologie [Paris]

Major depressive disorder is a complex multifactorial condition with a so far poorly characterized underlying pathophysiology. Consequently, the available treatments are far from satisfactory as it is estimated that up to 30% of patients are resistant to conventional treatment. Recent comprehensive evidence has been accumulated which suggests that inflammation may be implied in the etiology of this disease. Here we investigated ketamine as an innovative treatment strategy due to its immune-modulating capacities. In a murine model of LPS-induced depressive-like behavior we demonstrated that a single dose of ketamine restores the LPS-induced depressivelike alterations. These behavioral effects are associated with i/ a reversal of anxiety and reduced self-care, ii/ a decrease in parenchymal cytokine production, iii/ a modulation of the microglial reactivity and iv/ a decrease in microglial quinolinic acid production that is correlated with plasmatic peripheral production. In a translational approach, we show that kynurenic acid to quinolinic acid ratio is a predictor of ketamine response in treatmentresistant depressed patients and that the reduction in quinolinic acid after a ketamine infusion is a predictor of the reduction in MADRS score. Our results suggest that microglia is a key therapeutic target and that quinolinic acid is a biomarker of ketamine response in major depressive disorder.

Keywords: Biomarker; Depression; Inflammation; Ketamine; Microglia; Murine model; Quinolinic acid; Translational research

Domains: Life Sciences [q-bio]; Neurons and Cognition [q-bio.NC]; Neurobiology

Franck Verdonk, Anne-Cécile Petit, Pierre Abdel-Ahad, Fabien Vinckier, Gregory Jouvion, et al.. Microglial production of quinolinic acid as a target and a biomarker of the antidepressant effect of ketamine. Brain, Behavior, and Immunity, 2019, 81, pp.361 - 373. ⟨10.1016/j.bbi.2019.06.033⟩. ⟨pasteur-03263257⟩