Date of Award
Master of Science
Molecular Cellular and Systemic Physiology
Major depressive disorder (MDD) is a serious public health problem that is prevalent in the United States and all over the world. Despite the high incidence of MDD and its socioeconomic impact, the etiology of MDD remains largely unknown. Current traditional antidepressants used in clinical treatment are far from ideal. They usually take weeks to months to produce efficiency. And high risk of suicide is another factor to limit their application. Moreover, nearly 30% of the patients with depression are resistant to traditional antidepressant treatment. Recent evidence from clinical trials shows that a single subanesthesia dose (0.5-20 mg/kg) of ketamine, a noncompetitive ionotropic glutamatergic NMDA receptor antagonist, produces rapid antidepressant responses in patients suffering from MDD. However, recent studies on the mechanism underlying ketamine's fast-acting antidepressant effect are controversial. Moreover, the psychotomimetic properties and abuse potential of ketamine necessitate caution in promoting this compound as a general treatment for depression. Understanding the underlying mechanism of action of ketamine linked to behavioral improvement is of significant importance for developing novel, safe and fast-acting antidepressants. In the current study, we provide evidence to support a new hypothesis on how NMDA receptor blockage induces fast antidepressant effect, which is quite different from the prevalent theories about fast antidepressant action of ketamine.In this study we observed that ketamine potentiates the excitatory synaptic transmission by recording fEPSP and whole-cell EPSC, which is dependent on PKA activation. More AMPA GluR1 receptors expressed on membrane surface by ketamine-enhanced phosphorylation of GluR1 at site Ser845. Additionally for the upstream signaling of ketamine-induced potentiation of synaptic transmission, we found that ketamine blocks presynaptic NMDA receptors and decrease presynaptic HCN channel expressions which leads to an increase of presynaptic glutamate release, and thus enhanced postsynaptic responses by PKA activation pathways.
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