Long-term fluoxetine treatment induces input-specific LTP and LTD impairment and structural plasticity in the CA1 hippocampal subfield.
Open accessAbstract
Antidepressant drugs are usually administered for several weeks for the treatment of major depressive disorder. However, they are also prescribed in several additional psychiatric conditions as well as during long-term maintenance treatments. Antidepressants induce adaptive changes in several forebrain structures which include modifications at glutamatergic synapses. We recently found that repetitive administration of the selective serotonin reuptake inhibitor (SSRI) fluoxetine to naïve adult male rats induced an increase of mature, mushroom-type dendritic spines in several forebrain regions. This was associated with an increase of GluA2-containing α-amino-3-hydroxy-5-methylisoxazole-4-propionate receptors (AMPA-Rs) in telencephalic postsynaptic densities. To unravel the functional significance of such a synaptic re-arrangement, we focused on glutamate neurotransmission in the hippocampus. We evaluated the effect of four weeks of 0.7 mg/kg fluoxetine on long-term potentiation (LTP) and long-term depression (LTD) in the CA1 hippocampal subfield. Recordings in hippocampal slices revealed profound deficits in LTP and LTD at Schaffer collateral-CA1 synapses associated to increased spine density and enhanced presence of mushroom-type spines, as revealed by Golgi staining. However, the same treatment had neither an effect on spine morphology, nor on LTP and LTD at perforant path-CA1 synapses. Cobalt staining and immunohistochemical experiments revealed decreased AMPA-R Ca(2+) permeability in the stratum radiatum (s.r.) together with increased GluA2-containing Ca(2+) impermeable AMPA-Rs. Therefore, 4 weeks of fluoxetine treatment promoted structural and functional adaptations in CA1 neurons in a pathway-specific manner that were selectively associated with impairment of activity-dependent plasticity at Schaffer collateral-CA1 synapses.
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Long-term administration of fluoxetine at clinically relevant doses was associated with impaired dendritic spine morphology leading to deficits in hippocampal synaptic plasticity in an animal study.
“Worryingly, one recent animal study demonstrated that the long-term administration of fluoxetine at clinically relevant doses was associated with impaired dendritic spine morphology leading to deficits in hippocampal synaptic plasticity (Rubio et al., 2013).”
From Aerobic Exercise as a Tool to Improve Hippocampal Plasticity and Function in Humans: Practical Implications for Mental Health Treatment (2016) · cites this paper as Rubio et al., 2013
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“Worryingly, one recent animal study demonstrated that the long-term administration of fluoxetine at clinically relevant doses was associated with impaired dendritic spine morphology leading to deficits in hippocampal synaptic plasticity (Rubio et al., 2013).”
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- Authors
- Rubio, F. J., Ampuero, E., Sandoval, R., Toledo, J., Pancetti, F., & Wyneken, U.
- Affiliations
- Universidad de Los Andes, Chile (CL)
- Universidad Católica del Norte (CL)
- Venue
- Frontiers in Cellular Neuroscience
- Publisher
- Frontiers Media SA
- Published
- 2013
- Volume
- 7
- Pages
- 66-66
- ISSN
- 1662-5102 (ISSN-L)
- PMC
- PMC3648695
- OpenAlex
- W2040086852
- Cited by
- 54
- References
- 71
- Citations by year
- 2026: 4 · 2025: 1 · 2024: 2 · 2023: 4 · 2022: 3 · 2021: 4 · 2020: 4 · 2019: 5 · 2018: 4 · 2017: 6 · 2016: 5 · 2015: 8 · 2014: 4
- FWCI
- 2.78
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Frontiers in Cellular Neuroscience (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institutes of Health
- National Institute on Drug Abuse
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- fluoxetine, long-term potentiation, long-term depression, hippocampal CA1, Schaffer collateral-CA1 synapses, dendritic spines, mushroom spines, Ca2+-permeable AMPA receptors, structural plasticity, selective serotonin reuptake inhibitors, antidepressant effects, glutamatergic synapses, stratum radiatum
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