Attenuated palmitoylation of serotonin receptor 5-HT1A affects receptor function and contributes to depression-like behaviors

Nataliya Gorinski, Monika Bijata, Sonal Prasad, Alexander Wirth, Dalia Abdel Galil, Andre Zeug, Daria Bazovkina, Elena Kondaurova, Elizabeth Kulikova, Tatiana Ilchibaeva, Monika Zareba-Koziol, Francesco Papaleo, Diego Scheggia, Gaga Kochlamazashvili, Alexander Dityatev, Ian Smyth, Adam Krzystyniak, Jakub Wlodarczyk, Diethelm W. Richter, Tatyana Strekalova, Stephan Sigrist, Claudia Bang, Lisa Hobuß, Jan Fiedler, Thomas Thum, Vladimir S. Naumenko (), Ghanshyam Pandey () and Evgeni Ponimaskin ()
Additional contact information
Nataliya Gorinski: Hannover Medical School
Monika Bijata: Hannover Medical School
Sonal Prasad: Hannover Medical School
Alexander Wirth: Hannover Medical School
Dalia Abdel Galil: Hannover Medical School
Andre Zeug: Hannover Medical School
Daria Bazovkina: Institute of Cytology and Genetics
Elena Kondaurova: Institute of Cytology and Genetics
Elizabeth Kulikova: Institute of Cytology and Genetics
Tatiana Ilchibaeva: Institute of Cytology and Genetics
Monika Zareba-Koziol: Nencki Institute
Francesco Papaleo: Istituto Italiano di Tecnologia
Diego Scheggia: Istituto Italiano di Tecnologia
Gaga Kochlamazashvili: Istituto Italiano di Tecnologia
Alexander Dityatev: Istituto Italiano di Tecnologia
Ian Smyth: Monash University
Adam Krzystyniak: Nencki Institute
Jakub Wlodarczyk: Nencki Institute
Diethelm W. Richter: University of Göttingen
Tatyana Strekalova: Sechenov First Moscow State Medical University
Stephan Sigrist: Free University Berlin
Claudia Bang: Hannover Medical School
Lisa Hobuß: Hannover Medical School
Jan Fiedler: Hannover Medical School
Thomas Thum: Hannover Medical School
Vladimir S. Naumenko: Institute of Cytology and Genetics
Ghanshyam Pandey: University of Illinois
Evgeni Ponimaskin: Hannover Medical School

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: Abstract The serotonergic system and in particular serotonin 1A receptor (5-HT1AR) are implicated in major depressive disorder (MDD). Here we demonstrated that 5-HT1AR is palmitoylated in human and rodent brains, and identified ZDHHC21 as a major palmitoyl acyltransferase, whose depletion reduced palmitoylation and consequently signaling functions of 5-HT1AR. Two rodent models for depression-like behavior show reduced brain ZDHHC21 expression and attenuated 5-HT1AR palmitoylation. Moreover, selective knock-down of ZDHHC21 in the murine forebrain induced depression-like behavior. We also identified the microRNA miR-30e as a negative regulator of Zdhhc21 expression. Through analysis of the post-mortem brain samples in individuals with MDD that died by suicide we find that miR-30e expression is increased, while ZDHHC21 expression, as well as palmitoylation of 5-HT1AR, are reduced within the prefrontal cortex. Our study suggests that downregulation of 5-HT1AR palmitoylation is a mechanism involved in depression, making the restoration of 5-HT1AR palmitoylation a promising clinical strategy for the treatment of MDD.

Date: 2019
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DOI: 10.1038/s41467-019-11876-5

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