Cited by 175Treatment of Major DepressionNeuroscience and Neuropharmacology ResearchNeurotransmitter Receptor Influence on Behavior

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Fast-acting antidepressants rapidly stimulate ERK signaling and BDNF release in primary neuronal cultures

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Lepack, Ashley E., Bang, Eunyoung, Lee, Boyoung, Dwyer, Jason M., Duman, Ronald S.·2016·Neuropharmacology

DOI 10.1016/j.neuropharm.2016.09.011PMC PMC5075989

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Abstract

Recent preclinical and clinical studies demonstrate that three functionally different compounds, the NMDA receptor channel blocker ketamine, mGlu 2/3 receptor antagonist LY341495, and NMDA receptor glycine site agent GLYX-13 produce rapid and long lasting antidepressant effects. Furthermore, these agents are reported to stimulate ERK and mTORC1 signaling in brain. Here we used rat primary cortical culture neurons to further examine the cellular actions of these agents. The results demonstrate that low concentrations of all three compounds rapidly increase levels of the phosphorylated and activated forms of ERK and a downstream target of mTORC1, p70S6 kinase, in a concentration and time dependent manner. In addition, each compound rapidly increases BDNF release into the culture media. Further studies demonstrate that induction of BDNF release, as well as stimulation of phospho-ERK is blocked by incubation with an AMPA receptor antagonist. The requirement for AMPA receptor stimulation suggests that the effects of these rapid agents are activity dependent. This possibility is supported by studies demonstrating that neuronal silencing, via incubation with the GABA A receptor agonist muscimol, completely blocks phospho-ERK and BDNF release by each agent. Finally, incubation with each drug for 24 h increases the number and length of neuronal branches. Together, the results demonstrate that these three different rapid acting antidepressant agents increase ERK signaling and BDNF release in an activity dependent manner that leads to increased neuronal complexity. Further studies will be required to determine the exact mechanisms underlying these effects in cultured neurons and in rodent models.

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Authors: Lepack, A. E., Bang, E., Lee, B., Dwyer, J. M., & Duman, R. S.
Affiliations: Yale University (US)
Corresponding author: Duman, Ronald S.
ORCID: Lepack, Ashley E.
Bang, Eunyoung
Lee, Boyoung
Duman, Ronald S.
Venue: Neuropharmacology
Publisher: Elsevier BV
Published: 2016-12
Volume: 111
Pages: 242-252
ISSN: 0028-3908 (ISSN-L)
DOI: 10.1016/j.neuropharm.2016.09.011
PMC: PMC5075989
OpenAlex: W2518741199
Cited by: 174
References: 42
Citations by year: 2026: 7 · 2025: 14 · 2024: 15 · 2023: 20 · 2022: 23 · 2021: 18 · 2020: 20 · 2019: 24 · 2018: 20 · 2017: 13
FWCI: 15.38
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Neuropharmacology (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: NIMH (R37MH45481, R01MH93897)
State of Connecticut
Yale University
Topics: Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Keywords: rapid-acting antidepressants, ketamine, LY341495, ERK signaling, BDNF release, mTORC1, p70 S6 kinase, AMPA receptors, activity-dependent plasticity, neuronal morphology, cortical neurons, muscimol, GABAA receptor
MeSH terms: Amino Acids, Animals, Antidepressive Agents, Cells, Cultured, Cerebral Cortex, Dendrites, Ketamine, Oligopeptides, Xanthenes, Receptors, AMPA, Brain-Derived Neurotrophic Factor, Receptor, trkB, MAP Kinase Signaling System, Rats, GABAergic Neurons, Primary Cell Culture

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Fast-acting antidepressants rapidly stimulate ERK signaling and BDNF release in primary neuronal cultures

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