Depression is a debilitating mental disease, characterized by persistent low mood and anhedonia. Stress represents a major environmental risk factor for depression; the complex interaction of stress with genetic factors results in different individual vulnerability or resilience to the disorder. Dysfunctions of the glutamate system have a primary role in depression. Clinical neuroimaging studies have consistently reported alterations in volume and connectivity of cortico-limbic areas, where glutamate neurons and synapses predominate. This is confirmed by preclinical studies in rodents, showing that repeated stress induces morphological and functional maladaptive changes in the same brain regions altered in humans. Confirming the key role of glutamatergic transmission in depression, compelling evidence has shown that the non-competitive NMDA receptor antagonist, ketamine, induces, at sub-anesthetic dose, rapid and sustained antidepressant response in both humans and rodents.

We show here that the Chronic Mild Stress model of depression induces, only in stress-vulnerable rats, depressed-like anhedonic behavior, together with impairment of glutamate/GABA presynaptic release, BDNF mRNA trafficking in dendrites and dendritic morphology in hippocampus. Moreover, we show that a single administration of ketamine restores, in 24 h, normal behavior and most of the cellular/molecular maladaptive changes in vulnerable rats. Interestingly, ketamine treatment did not restore BDNF mRNA levels reduced by chronic stress but rescued dendritic trafficking of BDNF mRNA.

The present results are consistent with a mechanism of ketamine involving rapid restoration of synaptic homeostasis, through re-equilibration of glutamate/GABA release and dendritic BDNF for synaptic translation and reversal of synaptic and circuitry impairment.

抑郁症是一种使人衰弱的精神疾病，其特征在于持续的情绪低落和快感不足。压力是抑郁的主要环境危险因素。压力与遗传因素的复杂相互作用导致个体对疾病的脆弱性或适应力不同。谷氨酸系统的功能障碍在抑郁症中起主要作用。临床神经影像学研究一致地报告了谷氨酸神经元和突触占主导地位的皮质-边缘区域的体积和连通性发生了变化。在啮齿动物中的临床前研究证实了这一点，表明重复的压力会在人类改变的相同大脑区域诱发形态和功能适应不良的变化。证实了谷氨酸能传递在抑郁症中的关键作用，

我们在这里显示，抑郁的慢性轻度应激模型仅在易受应激的大鼠中诱发抑郁样的无性行为，以及谷氨酸/ GABA突触前释放的损伤，树突状细胞中BDNF mRNA的运输和海马树突状形态。此外，我们显示氯胺酮的单次给药可在24小时内恢复正常行为以及脆弱大鼠的大多数细胞/分子适应不良性变化。有趣的是，氯胺酮治疗不能恢复慢性应激降低的BDNF mRNA水平，但可以挽救BDNF mRNA的树突状运输。

目前的结果与氯胺酮涉及的机制有关，该机制涉及通过使谷氨酸/ GABA释放和树突状BDNF重新平衡以实现突触翻译以及逆转突触和电路障碍，从而快速恢复突触稳态。