The stress susceptibility factor FKBP51 controls S-ketamine-evoked release of mBDNF in the prefrontal cortex of mice

Elmira Anderzhanova; Kathrin Hafner; Andreas J Genewsky; Azza Soliman; Max L Pöhlmann; Mathias V Schmidt; Robert Blum; Carsten T Wotjak; Nils C Gassen

doi:10.1016/j.ynstr.2020.100239

The stress susceptibility factor FKBP51 controls S-ketamine-evoked release of mBDNF in the prefrontal cortex of mice

Neurobiol Stress. 2020 Jul 4:13:100239. doi: 10.1016/j.ynstr.2020.100239. eCollection 2020 Nov.

Authors

Elmira Anderzhanova^{1

2

3}, Kathrin Hafner⁴, Andreas J Genewsky^{5

6}, Azza Soliman^{5

7}, Max L Pöhlmann⁸, Mathias V Schmidt⁸, Robert Blum⁹, Carsten T Wotjak^{5

10}, Nils C Gassen^{1

4}

Affiliations

¹ Neurohomeostatis Research Group, Clinic of Psychiatry and Psychotherapy University Hospital Bonn, Venusberg-Campus 1, 53127, Bonn, Germany.
² Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Kraepelinst. 2-10, 80804, Munich, Germany.
³ BAU International University, Fridon Khalvashi st. 237, Batumi, 6010, Georgia.
⁴ Department of Translational Psychiatry, Max Planck Institute of Psychiatry, Kraepelinstraße 2-10, 80804, Munich, Germany.
⁵ Research Group Neuroplasticity, Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Kraepelinstr. 2-10, 80804 Munich, Germany.
⁶ Department Biology II Cognition and Neural Plasticity, Faculty of Medicine Ludwig-Maximilians Universität München, Großhaderner str. 2, 82152, Planegg-Martinsried, Germany.
⁷ Institute of Human Genetics University Medical Centre, Mainz Langenbeckstr, 155131 Mainz, Germany.
⁸ Research Group Neurobiology of Stress Resilience, Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Kraepelinstr. 2-10, 80804, Munich, Germany.
⁹ Institute of Clinical Neurobiology, University Hospital Würzburg, Versbacherstraße 2, 97080, Würzburg, Germany.
¹⁰ Boehringer Ingelheim Pharma GmbH & Co. KG, Dept. CNS Discovery Research, Birkendorfer Str. 65, 88397, Biberach an der Riß, Germany.

Abstract

We report here the involvement of the stress-responsive glucocorticoid receptor co-chaperone FKBP51 in the mechanism of in vivo secretion of mature BDNF (mBDNF). We used a novel method combining brain microdialysis with a capillary electrophoresis-based immunoassay, to examine mBDNF secretion in the medial prefrontal cortex (mPFC) in vivo in freely moving mice. By combining optogenetic, neurochemical (KCl-evoked depolarization), and transgenic (conditional BDNF knockout mice) means, we have shown that the increase in extracellular mBDNF in vivo is determined by neuronal activity. Withal, mBDNF secretion in the mPFC of mice was stimulated by a systemic administration of S-ketamine (10 or 50 mg/kg) or S-hydroxynorketamine (10 mg/kg). KCl- and S-ketamine-evoked mBDNF secretion was strongly dependent on the expression of FKBP51. Moreover, the inability of S-ketamine to evoke a transient secretion in mBDNF in the mPFC in FKBP51- knockout mice matched the lack of antidepressant-like effect of S-ketamine in the tail suspension test. Our data reveal a critical role of FKBP51 in mBDNF secretion and suggest the involvement of mBDNF in the realization of immediate stress-coping behavior induced by acute S-ketamine.

Keywords: BDNF; FKBP51; Ketamine; Microdialysis; Neuroplasticity; Stress susceptibility.