It remains unclear why many patients with depression do not respond to antidepressant treatment. In three cohorts of individuals with depression and treated with serotonin-norepinephrine reuptake inhibitor (N = 424) we show that responders, but not non-responders, display an increase of GPR56 mRNA in the blood. In a small group of subjects we also show that GPR56 is downregulated in the PFC of individuals with depression that died by suicide. In mice, we show that chronic stress-induced Gpr56 downregulation in the blood and prefrontal cortex (PFC), which is accompanied by depression-like behavior, and can be reversed by antidepressant treatment. Gpr56 knockdown in mouse PFC is associated with depressive-like behaviors, executive dysfunction and poor response to antidepressant treatment. GPR56 peptide agonists have antidepressant-like effects and upregulated AKT/GSK3/EIF4 pathways. Our findings uncover a potential role of GPR56 in antidepressant response.

尚不清楚为什么许多抑郁症患者对抗抑郁药治疗无效。在抑郁症的个体的三组，并用血清素-去甲肾上腺素再摄取抑制剂治疗（Ñ = 424），我们显示反应者而非血液反应者显示血液中GPR56 mRNA的增加。在一小部分受试者中，我们还显示GPR56在因自杀死亡的抑郁症患者的PFC中被下调。在小鼠中，我们表明，慢性应激诱导的血液和前额叶皮层（PFC）中的Gpr56下调，伴随着抑郁样行为，可以通过抗抑郁药逆转。小鼠PFC中的Gpr56敲低与抑郁样行为，执行功能障碍和对抗抑郁药治疗的不良反应有关。GPR56肽激动剂具有抗抑郁样作用，并且上调AKT / GSK3 / EIF4途径。我们的发现揭示了GPR56在抗抑郁反应中的潜在作用。