European Journal of Neuroscience
December 6, 2019
Ronald S. Duman, Satoshi Deyama, Manoela V. Fogaça
319 citations
Stress and depression cause neuron atrophy and reduced synaptic connectivity in the hippocampus and prefrontal cortex, contributing to depressive behaviors. Antidepressant treatment can reverse these deficits. Brain-derived neurotrophic factor (BDNF) is key: stress decreases BDNF expression in these regions, while antidepressants up-regulate it. Rapid-acting antidepressants like ketamine produce fast synaptic and behavioral effects dependent on activity-dependent BDNF release, unlike typical monoaminergic agents that require chronic administration for slow BDNF induction. Other rapid-acting agents also require BDNF release, indicating a convergent downstream mechanism. Ketamine's actions also depend on vascular endothelial growth factor (VEGF) and its interplay with BDNF.
Proceedings of the National Academy of Sciences
December 17, 2018
Kenichi Fukumoto, Manoela V. Fogaça, Rong-Jian Liu et al.
191 citations
A metabolite of ketamine, (2R,6R)-hydroxynorketamine [(2R,6R)-HNK], produces rapid and sustained antidepressant effects in animal models without the side effects of ketamine and without blocking the NMDA receptor. The antidepressant effects require activity-dependent release of BDNF, mediated by stimulation of voltage-dependent Ca2+ channels. Increased BDNF release activates downstream TrkB and mechanistic target of rapamycin complex 1 signaling, which increases synaptic function of pyramidal neurons in the medial prefrontal cortex. Stimulation of BDNF release and increased synaptic function block or reverse the detrimental effects of stress and depression.
Neurobiology of Disease
November 7, 2019
Sriparna Ghosal, Catharine H. Duman, Rong-Jian Liu et al.
94 citations
Chronic unpredictable stress in male rodents reduces GABAergic proteins and the frequency of inhibitory postsynaptic currents in layer V pyramidal neurons of the medial prefrontal cortex, accompanied by depression-like behaviors. A single dose of ketamine reverses these stress-induced deficits in GABA markers and depressive-like behaviors. The findings indicate that impairments of GABAergic synapses are key determinants of depressive behavior and that ketamine restores both GABA inhibitory and glutamate neurotransmission.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
March 1, 2025
Manoela V. Fogaça, Fernanda Daher, Marina R. Picciotto
22 citations
Ketamine produces sustained antidepressant effects in mice by first decreasing and later increasing the activity of GABA neurons in the medial prefrontal cortex. Calcium recordings showed an initial transient drop in GABA neuron activity lasting about 60 minutes, alongside a brief rise in excitation/inhibition balance and a longer-lasting increase in glutamatergic activity from 30 to 120 minutes. Previous ketamine treatment enhanced GABA neuron activity during behavioral tests 24 and 72 hours later. Chemogenetically inhibiting GABA interneurons during the later surge of activity or just before those tests blocked ketamine's behavioral effects. Thus, time-dependent modulation of GABAergic activity is necessary for ketamine's lasting antidepressant-like actions, pointing to GABAergic plasticity as a target for new antidepressants.
bioRxiv : the preprint server for biology
January 16, 2026
Fernanda Daher, Caio T Fukushima, Erik A Ingebretsen et al.
1 citation
A negative allosteric modulator of α5-GABA A receptors, Basmisanil (BSM), produces rapid and sustained improvements in motivation, pleasure-seeking, and active coping behaviors in mice, similar to ketamine but without its side effects. BSM activates specific cell types in the medial prefrontal cortex (mPFC) and engages signaling pathways (Erk, Akt-mTOR) that boost synaptic proteins for both glutamatergic and GABAergic function. It also reverses stress-induced impairments in memory and social interaction. Early activation of pyramidal neurons in the mPFC is necessary for BSM's rapid effects, while later GABAergic adaptations sustain long-term benefits, restoring excitation-inhibition balance and highlighting GABAergic targets for stress-related disorders.
Manoela V. Fogaça, Fernanda Daher, Marina R. Picciotto
preprint
Ketamine produces sustained antidepressant effects in mice by first decreasing then increasing the activity of GABA neurons in the medial prefrontal cortex. Calcium recordings showed an initial transient decrease in GABA neuron activity (phase 1, under 30 minutes) followed by an increase (phase 2, after 60 minutes), alongside a lasting enhancement of glutamatergic activity (30-120 minutes). Chemogenetic inhibition of GABA interneurons during phase 2 or before behavioral tests blocked ketamine's antidepressant actions. The findings indicate that time-dependent modulation of GABAergic activity is required for ketamine's sustained antidepressant-like responses, suggesting that enhancing GABAergic plasticity and function may be a promising therapeutic target.