期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：26
页码：8106-8111
DOI：10.1073/pnas.1414728112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceClinical studies report that a single, low dose of ketamine produces a rapid antidepressant response in treatment-resistant depressed patients. Although rodent studies have begun to elucidate the molecular mechanisms underlying the behavioral actions of ketamine, the brain regions and cellular mechanisms have not been defined. Using a combination of pharmacological silencing and optogenetic stimulation approaches, the results of the current study demonstrate that ketamine infusion or optogenetic stimulation of the infalimbic prefrontal cortex produces antidepressant behavioral and synaptic responses similar to the actions of systemic ketamine. These findings further elucidate the mechanisms underlying the therapeutic actions of ketamine and will enhance the development of safer rapid-acting and efficacious agents. Ketamine produces rapid and sustained antidepressant actions in depressed patients, but the precise cellular mechanisms underlying these effects have not been identified. Here we determined if modulation of neuronal activity in the infralimbic prefrontal cortex (IL-PFC) underlies the antidepressant and anxiolytic actions of ketamine. We found that neuronal inactivation of the IL-PFC completely blocked the antidepressant and anxiolytic effects of systemic ketamine in rodent models and that ketamine microinfusion into IL-PFC reproduced these behavioral actions of systemic ketamine. We also found that optogenetic stimulation of the IL-PFC produced rapid and long-lasting antidepressant and anxiolytic effects and that these effects are associated with increased number and function of spine synapses of layer V pyramidal neurons. The results demonstrate that ketamine infusions or optogenetic stimulation of IL-PFC are sufficient to produce long-lasting antidepressant behavioral and synaptic responses similar to the effects of systemic ketamine administration.
