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 StrekalovaStephan Sigrist, Claudia Bang, Lisa Hobuß, Jan Fiedler, Thomas Thum, Vladimir S. Naumenko, Ghanshyam Pandey, Evgeni Ponimaskin

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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.

Original languageEnglish
Article number3924
Number of pages14
JournalNature Communications
Issue number1
Publication statusPublished - 2 Sep 2019


  • depression
  • G protein-coupled receptors

Cite this

Gorinski, N., Bijata, M., Prasad, S., Wirth, A., Abdel Galil, D., Zeug, A., Bazovkina, D., Kondaurova, E., Kulikova, E., Ilchibaeva, T., Zareba-Koziol, M., Papaleo, F., Scheggia, D., Kochlamazashvili, G., Dityatev, A., Smyth, I., Krzystyniak, A., Wlodarczyk, J., Richter, D. W., ... Ponimaskin, E. (2019). Attenuated palmitoylation of serotonin receptor 5-HT1A affects receptor function and contributes to depression-like behaviors. Nature Communications, 10(1), [3924].