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.

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Catalepsy or pronounced freezing is a natural passive defense strategy in animals and a syndrome of some mental disorders in human. Hereditary catalepsy was shown to be associated with depressive‐like features in rats and mice. The loci underlying the difference in predisposition to catalepsy between catalepsy‐prone CBA/lacJ and catalepsy‐resistant AKR/J mice were mapped using congenic line and selective breeding approaches. Three congenic mouse lines (AKR.CBA‐D13Mit76C, AKR.CBA‐D13Mit76A and AKR.CBA‐D13Mit78) carrying the 59‐ to 70‐, 61‐ to 70‐ and 71‐ to 75‐cm fragments of chromosome 13 transferred from the CBA to the AKR genome were created by nine successive backcrossing of (CBA × AKR)F1 on AKR strain. Because catalepsy was found only in the AKR.CBA‐D13Mit76C and AKR.CBA‐D13Mit76A mice, the major gene of catalepsy was mapped on the fragment of 61–70 cm. Selective breeding of the (CBA × (CBA × AKR))BC backcross generation for high predisposition to catalepsy showed numerous genome‐wide distributed CBA‐derived alleles as well as the AKR‐derived alleles mapped on chromosome 17 and on the proximal parts of chromosomes 10 and 19 that increased the cataleptogenic effect of the major gene.

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