Ketamine regulates the presynaptic release machinery in the hippocampus
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In the search for new drug targets, that may help point the way to develop fast-acting treatments for mood disorders, we have explored molecular pathways regulated by ketamine, an NMDA receptor antagonist, which has consistently shown antidepressant response within a few hours of administration. Using Sprague-Dawley rats we investigated the effects of ketamine on the presynaptic release machinery responsible for neurotransmitter release at 1, 2 and 4 h as well as 7 days after administration of a single subanesthetic dose of ketamine (15 mg/kg). A large reduction in the accumulation of SNARE complexes was observed in hippocampal synaptic membranes after 1, 2 and 4 h of ketamine administration. In parallel, we found a selective reduction in the expression of the synaptic vesicle protein synaptotagmin I and an increase in the levels of synapsin I in hippocampal synaptosomes suggesting a mechanism by which ketamine reduces SNARE complex formation, in part, by regulating the number of synaptic vesicles in the nerve terminals. Moreover, ketamine reduced Thr(286)-phosphorylated αCaMKII and its interaction with syntaxin 1A, which identifies CaMKII as a potential target for second messenger-mediated actions of ketamine. In addition, despite previous reports of ketamine-induced inhibition of GSK-3, we were unable to detect regulation of its activity after ketamine administration. Our findings demonstrate that ketamine rapidly induces changes in the hippocampal presynaptic machinery similar to those that are obtained only with chronic treatments with traditional antidepressants. This suggests that reduction of neurotransmitter release in the hippocampus has possible relevance for the rapid antidepressant effect of ketamine.
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Müller et al. found S-ketamine alters the expression of proteins involved in release into the synaptic cleft 1, 2 and 4 h and 7 days after administration using immunoblotting in healthy Sprague Dawley rats.
“Previous studies have found S-ketamine to alter the expression of different proteins involved in release into the synaptic cleft 1, 2 and 4 h and 7 days after administration using immunoblotting in healthy Sprague Dawley rats (Müller et al., 2013).”
From A single subanaesthetic dose of the rapid-acting antidepressant S-ketamine raises presynaptic SV2A density in limbic regions of the Wistar Kyoto rat model of depression (2024) · cites this paper as Müller et al., 2013
Synaptotagmin 1 was not reduced until 2 and 4 h after S-ketamine, and synapsin 1 was not increased until 2 and 4 h as well as 7 days after administration.
“Yet, expression of synaptotagmin 1 was not reduced until 2 and 4 h after administration, and synapsin 1 was not increased until 2 and 4 h as well as 7 days after administration (Müller et al., 2013).”
From A single subanaesthetic dose of the rapid-acting antidepressant S-ketamine raises presynaptic SV2A density in limbic regions of the Wistar Kyoto rat model of depression (2024) · cites this paper as Müller et al., 2013
Previous studies found S-ketamine alters gene expression in the hippocampus.
“Regarding the real-time qPCR data, the hippocampus was investigated due to previous studies finding S-ketamine to alter gene expression in this region (Du Jardin et al., 2017; Müller et al., 2013).”
From A single subanaesthetic dose of the rapid-acting antidepressant S-ketamine raises presynaptic SV2A density in limbic regions of the Wistar Kyoto rat model of depression (2024) · cites this paper as Müller et al., 2013
The SNARE complex was reduced 1, 2 and 4 h after S-ketamine administration along with αCaMKII.
“Here, the SNARE complex facilitating fusion of vesicles with the presynaptic membrane preparing the release of neurotransmitters into the synaptic cleft was reduced 1, 2 and 4 h after administration of S-ketamine along with αCaMKII (Müller et al., 2013).”
From A single subanaesthetic dose of the rapid-acting antidepressant S-ketamine raises presynaptic SV2A density in limbic regions of the Wistar Kyoto rat model of depression (2024) · cites this paper as Müller et al., 2013
A single administration of ketamine significantly increases the number of synaptic vesicles as well as important synaptic structural proteins within hours of drug administration, persisting for about 7 days.
“a single administration of ketamine significantly increases the number of synaptic vesicles [101] as well as important synaptic structural proteins within hours of drug administration that persisted for about 7 days [30,95,101].”
From Challenges and rewards of in vivo synaptic density imaging, and its application to the study of depression (2025) · cites this paper as [101]
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- Authors
- Müller, H. K., Wegener, G., Liebenberg, N., Zarate, C. A., Popoli, M., & Elfving, B.
- Affiliations
- Aarhus University Hospital (DK)
- National Institutes of Health (US)
- University of Milan (IT)
- Corresponding author
- Müller, Heidi Kaastrup
- ORCID
- Venue
- Journal of Psychiatric Research
- Publisher
- Elsevier BV
- Published
- 2013-07
- Volume
- 47
- Issue
- 7
- Pages
- 892-899
- ISSN
- 0022-3956 (ISSN-L)
- PMC
- PMC3678963
- OpenAlex
- W2089066634
- Cited by
- 61
- References
- 57
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 5 · 2023: 6 · 2022: 4 · 2021: 6 · 2020: 2 · 2019: 5 · 2018: 1 · 2017: 5 · 2016: 7 · 2015: 7 · 2014: 5 · 2013: 4
- FWCI
- 5.64
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Psychiatric Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute of Mental Health (ZIAMH002927)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Psychiatry and Mental health › Electroconvulsive Therapy Studies
- Keywords
- ketamine, hippocampus, SNARE complex, synaptotagmin-1, synapsin I, synaptic vesicles, CaMKII, syntaxin 1A, glycogen synthase kinase-3, NMDA receptor antagonists, rapid antidepressant effects, mood disorders, neurotransmitter release
- MeSH terms
- Animals, Antidepressive Agents, Tricyclic, Desipramine, Gene Expression Regulation, Hippocampus, Ketamine, Male, Nerve Tissue Proteins, Swimming, Synaptosomes, Time Factors, Rats, Sprague-Dawley, Presynaptic Terminals, Excitatory Amino Acid Antagonists, Immunoprecipitation, SNARE Proteins, Synaptosomal-Associated Protein 25, Synaptotagmin I, Rats, Munc18 Proteins, Calcium-Calmodulin-Dependent Protein Kinase Type 2
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