Zhang Ke, Xu Ting, Yuan Zhongmin, Wei Zhisheng, Yamaki Vitor Nagai, Huang Mingfa, Huganir Richard L, Cai Xiang
Department of Physiology, Southern Illinois University School of Medicine, 1135 Lincoln Drive, Carbondale, IL 62901, USA.
The Institute of Neuroscience, the Second Affiliated Hospital of Guangzhou Medical University, 250 Changgang Road, Guangzhou, Guangdong 51030, China.
Sci Signal. 2016 Dec 13;9(458):ra123. doi: 10.1126/scisignal.aai7884.
Although the molecular mechanism is not clear, the clinically tested drug ketamine has rapid antidepressant action that does not require the multiple weeks of treatment needed for other antidepressant drugs to have an effect. We showed that ketamine potentiated Schaffer collateral-CA1 cell excitatory synaptic transmission in hippocampal slice preparations from rodents and enhanced the phosphorylation of the GluA1 subunit on Ser of the AMPA-type glutamate receptor in the hippocampal area CA1. These effects persisted when γ-aminobutyric acid (GABA) receptors were pharmacologically blocked. Ketamine reduced behavioral despair in wild-type mice but had no effect in GluA1 S845A knock-in mutant mice. Presynaptic (CA3 pyramidal cell), but not postsynaptic (CA1 pyramidal cell), deletion of N-methyl-d-aspartate (NMDA)-type glutamate receptors eliminated the ketamine-induced enhancement of excitatory synaptic transmission in hippocampal slices and the antidepressant actions of ketamine in mice. The synaptic and behavioral actions of ketamine were completely occluded by inhibition or deletion of the hyperpolarization-activated cyclic nucleotide-gated channel 1 (HCN1). Our results implicate presynaptic NMDA receptor inhibition followed by reduced activity of presynaptic HCN1 channels, which would result in an increase in glutamate release and postsynaptic glutamate receptor activity, as a mechanism of ketamine action. These data provide a mechanism for changes in synaptic activity that could explain the fast-acting antidepressant effects of this drug.
尽管分子机制尚不清楚，但经临床测试的药物氯胺酮具有快速抗抑郁作用，无需像其他抗抑郁药物那样经过数周治疗才起效。我们发现，氯胺酮可增强啮齿动物海马切片标本中Schaffer侧支 - CA1细胞的兴奋性突触传递，并增强海马CA1区AMPA型谷氨酸受体GluA1亚基Ser位点的磷酸化。当γ-氨基丁酸（GABA）受体被药理阻断时，这些作用仍然存在。氯胺酮可减轻野生型小鼠的行为绝望，但对GluA1 S845A基因敲入突变小鼠没有影响。删除突触前（CA3锥体细胞）而非突触后（CA1锥体细胞）的N-甲基-D-天冬氨酸（NMDA）型谷氨酸受体，可消除氯胺酮诱导的海马切片兴奋性突触传递增强以及氯胺酮在小鼠中的抗抑郁作用。抑制或删除超极化激活的环核苷酸门控通道1（HCN1）可完全阻断氯胺酮的突触和行为作用。我们的结果表明，突触前NMDA受体抑制，随后突触前HCN1通道活性降低，这将导致谷氨酸释放增加和突触后谷氨酸受体活性增强，是氯胺酮作用的一种机制。这些数据为突触活动变化提供了一种机制，可解释该药物的快速抗抑郁作用。
