Attenuated palmitoylation of serotonin receptor 5-HT1A affects receptor function and contributes to depression-like behaviors.
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ABSTRACT:
SUBMITTER: Gorinski N
PROVIDER: S-EPMC6718429 | biostudies-literature | 2019 Sep
REPOSITORIES: biostudies-literature
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Attenuated palmitoylation of serotonin receptor 5-HT1A affects receptor function and contributes to depression-like behaviors.
Gorinski Nataliya N Bijata Monika M Prasad Sonal S Wirth Alexander A Abdel Galil Dalia D Zeug Andre A Bazovkina Daria D Kondaurova Elena E Kulikova Elizabeth E Ilchibaeva Tatiana T Zareba-Koziol Monika M Papaleo Francesco F Scheggia Diego D Kochlamazashvili Gaga G Dityatev Alexander A Smyth Ian I Krzystyniak Adam A Wlodarczyk Jakub J Richter Diethelm W DW Strekalova Tatyana T Sigrist Stephan S Bang Claudia C Hobuß Lisa L Fiedler Jan J Thum Thomas T Naumenko Vladimir S VS Pandey Ghanshyam G Ponimaskin Evgeni E
Nature communications 20190902 1
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 kno ...[more]
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Project description:The serotonergic system and in particular serotonin 1A receptor (5-HT1AR) are critically implicated in major depressive disorder (MDD), although underlying mechanisms remain enigmatic. Here we demonstrated that 5-HT1AR is palmitoylated in human and rodent brains and identified ZDHHC21 as a major palmitoyl-transferase, whose depletion reduced palmitoylation and consequently signaling functions of 5-HT1AR. Two rodent models for depression show reduced brain ZDHHC21 expression in conjunction with attenuated 5-HT1AR palmitoylation. Moreover, selective knock-down of ZDHHC21 in murine forebrain by itself sufficed to provoke depressive symptoms, demonstrating a causal relationship between 5-HT1AR palmitoylation and depression. Regarding the underlying mechanism, we identified the microRNA miR-30e as a negative regulator of Zdhhc21 expression. By analysis of the post-mortem samples from suicide MDD victims we also found ZDHHC21 expression as well as palmitoylation of 5-HT1AR to be specifically reduced within the prefrontal cortex (PFC), a brain area critically involved in the pathogenesis of depressive symptoms. Our study provides evidence for transcriptional downregulation of 5-HT1AR palmitoylation as a central mechanism in the etiology of depression and even suicide, in effect making the restoration of 5-HT1AR palmitoylation a promising clinical strategy for the treatment of major depressive disorder.
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