Frontiers in Molecular Neuroscience
September 11, 2015
Elena Enosyreva, Anita E Autry, Ege Ekavalali et al.
51 citations
Ketamine, an NMDA receptor antagonist, produces rapid antidepressant effects in adults with major depressive disorder by blocking NMDA receptors, which inhibits eukaryotic elongation factor 2 kinase, leading to increased protein synthesis and synaptic potentiation in the hippocampus. In juvenile animals, ketamine failed to produce an antidepressant response in the novelty suppressed feeding and forced swim tests and did not trigger synaptic potentiation in hippocampal slices, unlike in slices from older animals (6–9 weeks old). The NMDA receptor antagonist AP5 similarly triggered synaptic potentiation in mature hippocampus, indicating that global competitive blockade of NMDA receptors is sufficient for this effect. These findings suggest that global NMDA receptor blockade in developmentally mature hippocampal synapses is necessary for ketamine's antidepressant efficacy.
Science (New York, N.Y.)
May 8, 2025
Z Zack Ma, Natalie J Guzikowski, Ji-Woon Kim et al.
44 citations
Repeated ketamine treatment to maintain its rapid antidepressant effect can cause side effects, so extending the benefit from a single dose is an unmet need. Ketamine strengthens connections at CA3-CA1 synapses in the hippocampus, which is thought to underlie its antidepressant action. By temporarily boosting ERK activity through blocking the DUSP6 enzyme, researchers enhanced this synaptic strengthening and extended the antidepressant-like behavioral effects of a single ketamine dose in mice to up to 2 months. These effects depended on the TrkB receptor in excitatory neurons. The findings suggest that targeting downstream signaling pathways could sustain ketamine's rapid antidepressant effects without repeated dosing.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
October 1, 2024
Michelle K Piazza, Ege T Kavalali, Lisa M Monteggia
21 citations
Synaptic plasticity includes both homeostatic and Hebbian mechanisms that regulate AMPA receptor activity and glutamatergic transmission. Ketamine, a rapidly acting antidepressant, induces homeostatic plasticity to increase glutamatergic transmission. This study demonstrates that Hebbian plasticity, specifically long-term potentiation (LTP), remains intact in synapses that have undergone homeostatic scaling induced by ketamine, whether delivered systemically or perfused onto hippocampal brain slices. In mice exposed to chronic corticosterone (CORT) to model stress, CORT produced an anhedonia-like behavior but did not impair LTP induction. CORT exposure also did not disrupt the interaction between homeostatic and Hebbian plasticity; synapses from CORT-exposed mice showed intact ketamine-induced plasticity followed by LTP. These findings explain how ketamine treatment for depression does not compromise learning and memory processes that rely on LTP.
European archives of psychiatry and clinical neuroscience
September 29, 2024
Ege T Kavalali, Lisa M Monteggia
4 citations
Ketamine's rapid antidepressant action works by driving synaptic plasticity mechanisms rather than altering neuronal circuitry or triggering neurogenesis. This discovery makes fast-acting treatments for mood disorders plausible. The review covers the authors' decade of research on the specific synaptic plasticity events that mediate these rapid effects, and discusses growing interest in alternative psychoactive compounds with similar properties.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
November 1, 2024
Ji-Woon Kim, Benjamin Kleinfelter, Ege T Kavalali et al.
3 citations
Ketamine, a rapidly acting antidepressant, works by restoring glutamate signaling in the hippocampus, countering the effects of a drug that induces depressed mood. Physostigmine, which triggers depression-like symptoms in humans, was found to cause long-term reduction of glutamate release in the mouse hippocampus. Ketamine rapidly re-establishes synaptic efficacy through postsynaptic signaling and masks the behavioral effects of physostigmine. The findings reveal that the synaptic mechanisms underlying mood changes differ from those behind antidepressant action, suggesting distinct pathways for neuropsychiatric disorders and their treatment.
iScience
June 20, 2025
Michelle K Piazza, Abigael R Weit, Ege T Kavalali et al.
2 citations
Ketamine's antidepressant effects depend on increasing brain-derived neurotrophic factor (BDNF) and activating its receptor TrkB in the hippocampus. Rett syndrome, caused by MECP2 mutations, involves reduced BDNF. In Mecp2 knockout mice, ketamine and a TrkB agonist, LM22A-4, enhance both excitatory and inhibitory synaptic plasticity through separate BDNF-TrkB pathways. MeCP2 normally stabilizes inhibitory neurotransmission; without it, ketamine causes sustained disinhibition. These findings reveal how MeCP2 shapes acute ketamine action and suggest mechanisms for ketamine-based Rett syndrome treatments.