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Attenuated Palmitoylation of Serotonin Receptor 5-HT1A Affects Receptor Function and Contributes to Depression-Like Behaviors

Breastfeeding medicine : the official journal of the Academy of Breastfeeding Medicine(2019)SCI 4区

Cellular Neurophysiology | Behavioural Neurogenomics | Cell Biophysics | Neuroscience and Brain Technologies | Anatomy & Developmental Biology | Neuro and Sensory Physiology | Sechenov First Moscow State Medical University | Institute of Biology | Institute of Molecular and Translational Therapeutic Strategies | Department of Psychiatry

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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.
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Depression,G protein-coupled receptors,Science,Humanities and Social Sciences,multidisciplinary
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要点】:本研究揭示了血清素受体5-HT1A的棕榈酰化修饰对其功能有影响,且这种修饰的减少与抑郁样行为有关,提出了通过恢复5-HT1A的棕榈酰化来治疗抑郁症的潜在策略。

方法】:研究者使用了人类和啮齿类大脑样本,通过蛋白质组学分析确认了ZDHHC21是主要的棕榈酰化酶,通过基因敲除和小鼠模型探讨了ZDHHC21对5-HT1A受体棕榈酰化和抑郁样行为的影响。

实验】:实验中使用了两种抑郁样行为的小鼠模型,发现这些模型中大脑ZDHHC21表达下降和5-HT1A受体棕榈酰化减少。通过敲低前脑中ZDHHC21的表达,研究者观察到了抑郁样行为的产生。在自杀性死亡的重度抑郁症患者的死后大脑样本中,研究者发现miR-30e表达上调,而ZDHHC21表达和5-HT1A受体的棕榈酰化水平下降。