Several preclinical studies have reported the rapid antidepressant effects of N-methyl-D-aspartate receptor (NMDAR) antagonists, although the underlying mechanisms are still unclear. Death-associated protein kinase 1 (DAPK1) couples GluN2B subunits at extrasynaptic sites to regulate NMDAR channel conductance. In the present study, we found that chronic unpredictable stress (CUS) induced extracellular glutamate accumulation, accompanied by an increase in the DAPK1-NMDAR interaction, the high expression of DAPK1 and phosphorylated GluN2B at Ser1303, a decrease in phosphorylated DAPK1 at Ser308 and synaptic protein deficits in the rat medial prefrontal cortex (mPFC). CUS also enhanced GluN2B-mediated NMDA currents and extrasynaptic responses that were induced by bursts of high-frequency stimulation, which may be associated with the loss of astrocytes and low expression of glutamate transporter-1 (GLT-1). The blockade of GLT-1 in the mPFC was sufficient to induce depressive-like behavior and cause similar molecular changes. Selective GluN2B antagonist, DAPK1 knockdown by adeno-associated virus-mediated short-hairpin RNA or a pharmacological inhibitor, and the uncoupling of DAPK1 from the NMDAR GluN2B subunit produced rapid antidepressant-like effects and reversed CUS-induced alterations in the mPFC. The inhibition of DAPK1 and its interaction with GluN2B subunit in the mPFC also rescued CUS-induced depressive-like behavior 7 days after treatment. A selective GluN2B antagonist did not have rewarding effects in the conditioned place preference paradigm. Altogether, our findings suggest that the DAPK1 interaction with the NMDAR GluN2B subunit acts as a critical component in the pathophysiology of depression and is a potential target for new antidepressant treatments.

中文翻译：

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将DAPK1与NMDA受体GluN2B亚基解偶联，可产生类似抗抑郁药的快速作用。

几项临床前研究报告了N-甲基-D-天冬氨酸受体（NMDAR）拮抗剂的快速抗抑郁作用，尽管其潜在机制尚不清楚。死亡相关的蛋白激酶1（DAPK1）在突触外位点耦合GluN2B亚基，以调节NMDAR通道电导。在本研究中，我们发现慢性不可预测的压力（CUS）诱导细胞外谷氨酸积累，伴随着DAPK1-NMDAR相互作用的增加，Ser1303的DAPK1和磷酸化的GluN2B的高表达，Ser308的磷酸化的DAPK1和突触的减少大鼠内侧前额叶皮层（mPFC）中的蛋白质缺乏症。CUS还增强了GluN2B介导的NMDA电流和由高频刺激爆发诱导的突触外反应，这可能与星形胶质细胞的丢失和谷氨酸转运蛋白-1（GLT-1）的低表达有关。在mPFC中对GLT-1的阻断足以诱导类似抑郁的行为并引起类似的分子变化。选择性GluN2B拮抗剂，腺相关病毒介导的短发夹RNA或药理抑制剂对DAPK1的抑制作用以及DAPK1与NMDAR GluN2B亚基的解偶联作用产生了快速的抗抑郁样作用，并逆转了CUS诱导的mPFC改变。DAPK1的抑制及其在mPFC中与GluN2B亚基的相互作用也挽救了治疗后7天CUS诱导的抑郁样行为。选择性GluN2B拮抗剂在条件性位置偏爱范式中没有奖励作用。共，