The 5-HT1AR couples to a variety of effectors via pertussis toxin-sensitive heterotrimeric G proteins of the G i/o family, leading to the agonist-promoted adenylyl cyclase inhibition and a subsequent decrease of the cAMP level 9. Despite much effort, the molecular routes impairing the serotonin system in clinical depression and suicide remain largely enigmatic. It has been also demonstrated that decreased level of 5-HT1AR can lead to anxiety and stress disorders in mice and primates 7, 8. These data suggest an important role of postsynaptic 5-HT1AR in psychiatric disorders 6. The overexpression of the 5-HT1AR induced during the early postnatal period in the forebrain, but not in the raphe nuclei, has been found to be sufficient to rescue the behavioral phenotype of the knockout mice. It has been shown that 5-HT1AR-deficient mice demonstrate increased anxiety-related responses, fear conditioning, and increased freezing behavior 5. 5-HT1AR is involved in the regulation of states of depression and anxiety 4. Dysregulation of the serotonin system has long been considered central to the etiology of MDD, and the main inhibitory serotonin receptor 5-HT1A (5-HT1AR) seems to play a key role in depressive neuropathology 2, 3 (Supplementary Fig.

MDD often leads to suicide, with approximately 800,000 people who die are due to suicide every year 1. Major depressive disorder (MDD) is a prevalent mental illness associated with mortality and secondary morbidity. Our study suggests that downregulation of 5-HT1AR palmitoylation is a mechanism involved in depression, making the restoration of 5-HT1AR palmitoylationВ a promising clinical strategy for the treatment of MDD. 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. We also identified the microRNA miR-30e as a negative regulator of Zdhhc21 expression. Moreover, selective knock-down of ZDHHC21 inВ the murine forebrain induced depression-like behavior. Two rodent models for depression-like behavior show reduced brain ZDHHC21 expression and attenuated 5-HT1AR palmitoylation. Here we demonstrated that 5-HT1AR is palmitoylated in human and rodent brains, and identified ZDHHC21 as a major palmitoylВ acyltransferase, whose depletion reduced palmitoylation and consequently signaling functions of 5-HT1AR.

The serotonergic system and in particular serotonin 1A receptor (5-HT1AR) are implicated in major depressive disorder (MDD). Nature Communications volumeВ 10, ArticleВ number: 3924 ( 2019) Attenuated palmitoylation of serotonin receptor 5-HT1A affects receptor function and contributes to depression-like behaviors

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