Department of Physiology and Pharmacology, University of Western Ontario, London, ON, Canada.
Robarts Research Institute, University of Western Ontario, London, ON, Canada.
Mol Psychiatry. 2021 Nov;26(11):6688-6703. doi: 10.1038/s41380-021-01082-5. Epub 2021 May 12.
Ketamine is a dissociative anesthetic drug, which has more recently emerged as a rapid-acting antidepressant. When acutely administered at subanesthetic doses, ketamine causes cognitive deficits like those observed in patients with schizophrenia, including impaired working memory. Although these effects have been linked to ketamine's action as an N-methyl-D-aspartate receptor antagonist, it is unclear how synaptic alterations translate into changes in brain microcircuit function that ultimately influence cognition. Here, we administered ketamine to rhesus monkeys during a spatial working memory task set in a naturalistic virtual environment. Ketamine induced transient working memory deficits while sparing perceptual and motor skills. Working memory deficits were accompanied by decreased responses of fast spiking inhibitory interneurons and increased responses of broad spiking excitatory neurons in the lateral prefrontal cortex. This translated into a decrease in neuronal tuning and information encoded by neuronal populations about remembered locations. Our results demonstrate that ketamine differentially affects neuronal types in the neocortex; thus, it perturbs the excitation inhibition balance within prefrontal microcircuits and ultimately leads to selective working memory deficits.
氯胺酮是一种分离麻醉剂，最近已被发现具有快速抗抑郁作用。在亚麻醉剂量下急性给药时，氯胺酮会引起认知缺陷，类似于精神分裂症患者的认知缺陷，包括工作记忆受损。尽管这些影响与氯胺酮作为 N-甲基-D-天冬氨酸受体拮抗剂的作用有关，但尚不清楚突触改变如何转化为影响认知的大脑微电路功能的变化。在这里，我们在自然虚拟环境中进行的空间工作记忆任务期间给恒河猴施用氯胺酮。氯胺酮诱导了短暂的工作记忆缺陷，而不影响知觉和运动技能。工作记忆缺陷伴随着外侧前额叶皮层中快速放电抑制性中间神经元的反应减少和宽放电兴奋性神经元的反应增加。这转化为神经元调谐和神经元群体对记忆位置编码的信息减少。我们的结果表明，氯胺酮会在新皮层中以不同的方式影响神经元类型；因此，它扰乱了前额叶微电路内的兴奋抑制平衡，最终导致选择性工作记忆缺陷。
