Fogaça Manoela V, Daher Fernanda, Picciotto Marina R
Department of Pharmacology and Physiology, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642, USA.
Department of Psychiatry, Yale University School of Medicine, 34 Park Street, New Haven, CT 06519, USA.
bioRxiv. 2024 Jul 30:2024.07.29.605610. doi: 10.1101/2024.07.29.605610.
Major depressive disorder (MDD) is associated with disruptions in glutamatergic and GABAergic activity in the medial prefrontal cortex (mPFC), leading to altered synaptic formation and function. Low doses of ketamine rapidly rescue these deficits, inducing fast and sustained antidepressant effects. While it is suggested that ketamine produces a rapid glutamatergic enhancement in the mPFC, the temporal dynamics and the involvement of GABA interneurons in its sustained effects remain unclear. Using simultaneous photometry recordings of calcium activity in mPFC pyramidal and GABA neurons, as well as chemogenetic approaches in mice, we explored the hypothesis that initial effects of ketamine on glutamate signaling trigger subsequent enhancement of GABAergic responses, contributing to its sustained antidepressant responses. Calcium recordings revealed a biphasic effect of ketamine on activity of mPFC GABA neurons, characterized by an initial transient decrease (phase 1, <30 min) followed by an increase (phase 2, >60 min), in parallel with a transient increase in excitation/inhibition levels (10 min) and lasting enhancement of glutamatergic activity (30-120 min). Previous administration of ketamine enhanced GABA neuron activity during the sucrose splash test (SUST) and novelty suppressed feeding test (NSFT), 24 h and 72 h post-treatment, respectively. Chemogenetic inhibition of GABA interneurons during the surge of GABAergic activity (phase 2), or immediately before the SUST or NSFT, occluded ketamine's behavioral actions. These results indicate that time-dependent modulation of GABAergic activity is required for the sustained antidepressant-like responses induced by ketamine, suggesting that approaches to enhance GABAergic plasticity and function are promising therapeutic targets for antidepressant development.
重度抑郁症（MDD）与内侧前额叶皮质（mPFC）中谷氨酸能和γ-氨基丁酸能（GABAergic）活动的紊乱有关，导致突触形成和功能改变。低剂量氯胺酮可迅速纠正这些缺陷，产生快速且持久的抗抑郁作用。虽然有人认为氯胺酮能在mPFC中迅速增强谷氨酸能，但GABA中间神经元在其持久作用中的时间动态变化及参与情况仍不清楚。我们通过同时记录mPFC锥体神经元和GABA神经元的钙活性光度测量，以及在小鼠中采用化学遗传学方法，探讨了氯胺酮对谷氨酸信号的初始作用触发随后GABA能反应增强，从而促成其持久抗抑郁反应的假说。钙记录显示氯胺酮对mPFC GABA神经元的活动有双相作用，其特征是最初短暂下降（第1阶段，<30分钟），随后上升（第2阶段，>60分钟），同时兴奋/抑制水平短暂增加（10分钟），谷氨酸能活动持续增强（30 - 120分钟）。预先给予氯胺酮分别在治疗后24小时和72小时的蔗糖喷洒试验（SUST）和新奇抑制摄食试验（NSFT）中增强了GABA神经元活动。在GABA能活动激增期间（第2阶段）或在SUST或NSFT之前立即对GABA中间神经元进行化学遗传学抑制，阻断了氯胺酮的行为效应。这些结果表明，氯胺酮诱导的持久抗抑郁样反应需要GABA能活动的时间依赖性调节，这表明增强GABA能可塑性和功能的方法是抗抑郁药物开发中很有前景的治疗靶点。
