Disrupting phosphorylation of Tyr-1070 at GluN2B selectively produces resilience to depression-like behaviors
Disrupting phosphorylation of Tyr-1070 at GluN2B selectively produces resilience to depression-like behaviors
复制标题
破坏 GluN2B 上 Tyr-1070 的磷酸化选择性地产生对抑郁样行为的恢复能力
DOI：
10.1016/j.celrep.2021.109612
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发表时间：
2021-08-24
期刊：
影响因子：
8.8
通讯作者：
Yang，Wei
中科院分区：
文献类型：
--
作者：
Shi，Xiaofang;Zhang，Qi;Yang，Wei
靶向N-甲基-D-天冬氨酸受体（NMDAR）的药物已被批准用于治疗重度抑郁症（MDD）;然而，不良拟精神病和认知副作用的存在可能会限制其效用。在这项研究中，我们表明，在急性和慢性束缚应激（CRS）暴露后，小鼠GluN 2B亚基酪氨酸（Y）1070的磷酸化水平增加。通过Y1070 F突变敲入防止GluN 2B-Y1070磷酸化产生与抗抑郁药相似的效果，但不影响受试小鼠的认知或焦虑相关行为。从机制上讲，Y1070 F突变选择性地减少非突触NMDAR电流，并增加内侧前额叶皮层（mPFC）的第5层锥体神经元中的兴奋性突触的数量，但不增加海马中的兴奋性突触的数量。总而言之，我们的研究确定了mPFC中GluN 2B-Y1070的磷酸化水平作为一个动态的，保护抑郁行为的主开关，这表明破坏GluN 2B亚基的Y1070磷酸化具有开发新的抗抑郁药的潜力。
Drugs targeting N-methyl-D-aspartate receptors (NMDARs) have been approved to treat major depressive disorder (MDD); however, the presence of undesirable psychotomimetic and cognitive side effects may limit their utility. In this study, we show that the phosphorylation levels of the GluN2B subunit at tyrosine (Y) 1070 increase in mice after both acute and chronic restraint stress (CRS) exposure. Preventing GluN2B-Y1070 phosphorylation via Y1070F mutation knockin produces effects similar to those of antidepressants but does not affect cognitive or anxiety-related behaviors in subject mice. Mechanistically, the Y1070F mutation selectively reduces non-synaptic NMDAR currents and increases the number of excitatory synapses in the layer 5 pyramidal neurons of medial prefrontal cortex (mPFC) but not in the hippocampus. Altogether, our study identifies phosphorylation levels of GluN2B-Y1070 in the mPFC as a dynamic, master switch guarding depressive behaviors, suggesting that disrupting the Y1070 phosphorylation of GluN2B subunit has the potential for developing new antidepressants.