Chronic fluoxetine treatment alters the structure, connectivity and plasticity of cortical interneurons
Open accessAbstract
Novel hypotheses suggest that antidepressants, such as the selective serotonin reuptake inhibitor fluoxetine, induce neuronal structural plasticity, resembling that of the juvenile brain, although the underlying mechanisms of this reopening of the critical periods still remain unclear. However, recent studies suggest that inhibitory networks play an important role in this structural plasticity induced by fluoxetine. For this reason we have analysed the effects of a chronic fluoxetine treatment in the hippocampus and medial prefrontal cortex (mPFC) of transgenic mice displaying eGFP labelled interneurons. We have found an increase in the expression of molecules related to critical period plasticity, such as the polysialylated form of the neural cell adhesion molecule (PSA-NCAM), GAD67/65 and synaptophysin, as well as a reduction in the number of parvalbumin expressing interneurons surrounded by perineuronal nets. We have also described a trend towards decrease in the perisomatic inhibitory puncta on pyramidal neurons in the mPFC and an increase in the density of inhibitory puncta on eGFP interneurons. Finally, we have found that chronic fluoxetine treatment affects the structure of interneurons in the mPFC, increasing their dendritic spine density. The present study provides evidence indicating that fluoxetine promotes structural changes in the inhibitory neurons of the adult cerebral cortex, probably through alterations in plasticity-related molecules of neurons or the extracellular matrix surrounding them, which are present in interneurons and are known to be crucial for the development of the critical periods of plasticity in the juvenile brain.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Fluoxetine increases the expression of PSA-NCAM in the prefrontal cortex and alters the structure, connectivity, and plasticity of cortical interneurons.
“Fluoxetine was demonstrated to increase the expression of PSA-NCAM in the prefrontal cortex, and alter the structure connectivity and plasticity of cortical interneurons.(Guirado et al., 2014;Varea et al., 2007).”
From Serotonin and neuroplasticity – Links between molecular, functional and structural pathophysiology in depression (2017) · cites this paper as Guirado et al., 2014
The Discussion reports fluoxetine-related changes in interneuron connectivity and structure, and the mPFC spine-density results show a significant increase in interneuron dendritic spines. But this study found only a non-significant trend toward increased PSA-NCAM expression in the mPFC, not a demonstrated increase. Its References list Varea et al. (2007a) as the study reporting that increase. (LLM, conf=0.90)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus
Malberg, J. E., Eisch, A. J., Nestler, E. J., & Duman, R. S. (2000) · The Journal of Neuroscience · doi:10.1523/jneurosci.20-24-09104.2000 · Cited by 3,111 · see citing works
Interneurons of the neocortical inhibitory system
Markram, H., Toledo-Rodriguez, M., Wang, Y., Gupta, A., Silberberg, G., & Wu, C. (2004) · Nature Reviews Neuroscience · doi:10.1038/nrn1519 · Cited by 2,954 · see citing works
Critical period plasticity in local cortical circuits
Hensch, T. K. (2005) · Nature Reviews Neuroscience · doi:10.1038/nrn1787 · Cited by 2,323 · see citing works
Reactivation of Ocular Dominance Plasticity in the Adult Visual Cortex
Pizzorusso, T., Medini, P., Berardi, N., Chierzi, S., Fawcett, J. W., & Maffei, L. (2002) · Science · doi:10.1126/science.1072699 · Cited by 1,679 · see citing works
The antidepressant fluoxetine restores plasticity in the adult visual cortex
Vetencourt, J. F. M., Sale, A., Viegi, A., Baroncelli, L., De Pasquale, R., F. O'Leary, O., Castrén, E., & Maffei, L. (2008) · Science · doi:10.1126/science.1150516 · Cited by 890 · see citing works
Neuronal plasticity and survival in mood disorders
Duman, R. S., Malberg, J., Nakagawa, S., & D’Sa, C. (2000) · Biological Psychiatry · doi:10.1016/s0006-3223(00)00935-5 · Cited by 652 · see citing works
Removing brakes on adult brain plasticity: From molecular to behavioral interventions
Bavelier, D., Levi, D. M., Li, R. W., Dan, Y., & Hensch, T. K. (2010) · The Journal of Neuroscience · doi:10.1523/jneurosci.4812-10.2010 · Cited by 589 · see citing works
Polysialic acid in the plasticity of the developing and adult vertebrate nervous system
Rutishauser, U. (2008) · Nature Reviews Neuroscience · doi:10.1038/nrn2285 · Cited by 584 · see citing works
Castrén, E. (2005) · Nature Reviews Neuroscience · doi:10.1038/nrn1629 · Cited by 563 · see citing works
Self-citationThe dual role of the extracellular matrix in synaptic plasticity and homeostasis
Dityatev, A., Schachner, M., & Sonderegger, P. (2010) · Nature Reviews Neuroscience · doi:10.1038/nrn2898 · Cited by 559 · see citing works
Oliva, A. A., Jiang, M., Lam, T., Smith, K. L., & Swann, J. W. (2000) · The Journal of Neuroscience · doi:10.1523/jneurosci.20-09-03354.2000 · Cited by 498 · see citing works
Sanacora, G., Mason, G. F., Rothman, D. L., & Krystal, J. H. (2002) · American Journal of Psychiatry · doi:10.1176/appi.ajp.159.4.663 · Cited by 495 · see citing works
Fear erasure in mice requires synergy between antidepressant drugs and extinction training
Karpova, N. N., Pickenhagen, A., Lindholm, J., Tiraboschi, E., Kulesskaya, N., Ágústsdóttir, A., Antila, H., Popova, D., Akamine, Y., Sullivan, R., et al. (2011) · Science · doi:10.1126/science.1214592 · Cited by 382 · see citing works
Self-citationStress, cognitive impairment and cell adhesion molecules
Sandi, C. (2004) · Nature reviews. Neuroscience · doi:10.1038/nrn1555 · Cited by 374 · see citing works
Sensory Deprivation Alters Aggrecan and Perineuronal Net Expression in the Mouse Barrel Cortex
McRae, P. A., Rocco, M. M., Kelly, G., Brumberg, J. C., & Matthews, R. T. (2007) · The Journal of Neuroscience · doi:10.1523/jneurosci.5425-06.2007 · Cited by 272 · see citing works
Hajszán, T., MacLusky, N. J., & Leranth, C. (2005) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2005.03968.x · Cited by 239 · see citing works
Structural basis for the role of inhibition in facilitating adult brain plasticity
Chen, J. L., Lin, W. C., Cha, J. W., So, P. T., Kubota, Y., & Nedivi, E. (2011) · Nature Neuroscience · doi:10.1038/nn.2799 · Cited by 214 · see citing works
Reversal of hippocampal neuronal maturation by serotonergic antidepressants
Kobayashi, K., Ikeda, Y., Sakai, A., Yamasaki, N., Haneda, E., Miyakawa, T., & Suzuki, H. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0912690107 · Cited by 212 · see citing works
Di Cristo, G., Chattopadhyaya, B., Kuhlman, S. J., Fu, Y., Bélanger, M.-C., Wu, C. Z., Rutishauser, U., Maffei, L., & Huang, Z. J. (2007) · Nature Neuroscience · doi:10.1038/nn2008 · Cited by 201 · see citing works
Brückner, G., Seeger, G., Brauer, K., Härtig, W., Kacza, J., & Bigl, V. (1994) · Brain Research · doi:10.1016/s0006-8993(09)90012-9 · Cited by 132 · see citing works
Chronic stress alters inhibitory networks in the medial prefrontal cortex of adult mice
Gilabert-Juan, J., Castillo-Gomez, E., Guirado, R., Moltó, M. D., & Nacher, J. (2013) · Brain Structure and Function · doi:10.1007/s00429-012-0479-1 · Cited by 125 · see citing works
Self-citationNowicka, D., Soulsby, S., Skangiel‐Kramska, J., & Glazewski, S. (2009) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2009.06996.x · Cited by 110 · see citing works
Oltmann‐Norden, I., Galuska, S. P., Hildebrandt, H., Geyer, R., Gerardy‐Schahn, R., Geyer, H., & Mühlenhoff, M. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m708463200 · Cited by 108 · see citing works
Lévesque, M. (1998) · Cerebral Cortex · doi:10.1093/cercor/8.7.602 · Cited by 100 · see citing works
Gómez‐Climent, M. Á., Guirado, R., Castillo-Gómez, E., Varea, E., Gutièrrez‐Mecinas, M., Gilabert‐Juan, J., García-Mompó, C., Vidueira, S., Sanchez-Mataredona, D., Hernández-González, S., et al. (2010) · Cerebral Cortex · doi:10.1093/cercor/bhq177 · Cited by 97 · see citing works
Self-citationChronic fluoxetine treatment increases the expression of PSA-NCAM in the medial prefrontal cortex
Varea, E., Blasco-Ibáñez, J. M., Gómez-Climent, M. Á., Castillo-Gómez, E., Crespo, C., Martínez-Guijarro, F. J., & Nácher, J. (2007) · Neuropsychopharmacology · doi:10.1038/sj.npp.1301183 · Cited by 96 · see citing works
Involvement of endocannabinoids in antidepressant and anti-compulsive effect of fluoxetine in mice
Umathe, S. N., Manna, S. S. S., & Jain, N. S. (2011) · Behavioural Brain Research · doi:10.1016/j.bbr.2011.04.031 · Cited by 96 · see citing works
Cortical organization in shrews: Evidence from five species
Catania, K. C., Lyon, D. C., Mock, O. B., & Kaas, J. H. (1999) · The Journal of Comparative Neurology · doi:10.1002/(sici)1096-9861(19990719)410:1 · Cited by 90 · see citing works
Addition of the α2-Antagonist Yohimbine to Fluoxetine: Effects on Rate of Antidepressant Response
Sanacora, G., Berman, R., Cappiello, A., Oren, D. A., Kugaya, A., Liu, N., Gueorguieva, R. V., Fasula, D., & Charney, D. S. (2004) · Neuropsychopharmacology · doi:10.1038/sj.npp.1300418 · Cited by 79 · see citing works
Yu, H.-L., Deng, X., Li, Y.-J., Li, Y., Quan, Z., & Sun, X. (2011) · Pharmacological Reports · doi:10.1016/s1734-1140(11)70596-5 · Cited by 75 · see citing works
PSA-NCAM expression in the rat medial prefrontal cortex
Varea, E., Nácher, J., Blasco‐Ibáñez, J. M., Gómez‐Climent, M. Á., Castillo-Gómez, E., Crespo, C., & Martinez-Guijarro, F. J. (2005) · Neuroscience · doi:10.1016/j.neuroscience.2005.08.009 · Cited by 72 · see citing works
Yamada, J., & Jinno, S. (2013) · Neuroscience · doi:10.1016/j.neuroscience.2013.08.061 · Cited by 71 · see citing works
Distribution of PSA-NCAM expression in the amygdala of the adult rat
Nácher, J., Lanuza, E., & McEwen, B. S. (2002) · Neuroscience · doi:10.1016/s0306-4522(02)00219-1 · Cited by 71 · see citing works
Guirado, R., Sanchez-Matarredona, D., Varea, E., Crespo, C., Blasco‐Ibáñez, J. M., & Nácher, J. (2012) · BMC Neuroscience · doi:10.1186/1471-2202-13-5 · Cited by 70 · see citing works
Self-citationHowell, M. D., & Gottschall, P. E. (2012) · Neuroscience · doi:10.1016/j.neuroscience.2012.05.034 · Cited by 66 · see citing works
Varea, E., Castillo-Gómez, E., Gómez‐Climent, M. Á., Blasco‐Ibáñez, J. M., Crespo, C., Martinez-Guijarro, F. J., & Nácher, J. (2007) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2007.01.001 · Cited by 62 · see citing works
Kurosawa, N., Yoshida, Y., Kojima, N., & Tsuji, S. (1997) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1997.69020494.x · Cited by 61 · see citing works
The Dendritic Spines of Interneurons Are Dynamic Structures Influenced by PSA-NCAM Expression
Guirado, R., Pérez-Rando, M., Sanchez-Matarredona, D., Castillo-Gómez, E., Liberia, T., Rovira-Esteban, L., Varea, E., Crespo, C., Blasco‐Ibáñez, J. M., & Nácher, J. (2013) · Cerebral Cortex · doi:10.1093/cercor/bht156 · Cited by 58 · see citing works
Self-citationNon-granule PSA-NCAM immunoreactive neurons in the rat hippocampus
Nácher, J., Blasco‐Ibáñez, J. M., & McEwen, B. S. (2002) · Brain Research · doi:10.1016/s0006-8993(01)03365-0 · Cited by 54 · see citing works
Rubio, F. J., Ampuero, E., Sandoval, R., Toledo, J., Pancetti, F., & Wyneken, U. (2013) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2013.00066 · Cited by 54 · see citing works
Direct Alteration of a Specific Inhibitory Circuit of the Hippocampus by Antidepressants
Méndez, P., Pazienti, A., Szabó, G., & Bacci, A. (2012) · The Journal of Neuroscience · doi:10.1523/jneurosci.1720-12.2012 · Cited by 53 · see citing works
Castillo-Gómez, E., Varea, E., Blasco‐Ibáñez, J. M., Crespo, C., & Nácher, J. (2011) · PLoS ONE · doi:10.1371/journal.pone.0029516 · Cited by 45 · see citing works
Guirado, R., Varea, E., Castillo-Gómez, E., Gómez‐Climent, M. Á., Rovira-Esteban, L., Blasco‐Ibáñez, J. M., Crespo, C., Martinez-Guijarro, F. J., & Nácher, J. (2009) · Neuroscience Letters · doi:10.1016/j.neulet.2009.03.104 · Cited by 41 · see citing works
Self-citationExpression of the neural cell adhesion molecule and polysialic acid during early mouse embryogenesis
Probstmeier, R., Bilz, A., & Schneider‐Schaulies, J. (1994) · Journal of Neuroscience Research · doi:10.1002/jnr.490370305 · Cited by 41 · see citing works
Gene Expression Patterns Underlying the Reinstatement of Plasticity in the Adult Visual System
Tiraboschi, E., Guirado, R., Greco, D., Auvinen, P., Maya‐Vetencourt, J. F., Maffei, L., & Ċastrén, E. (2013) · Neural Plasticity · doi:10.1155/2013/605079 · Cited by 21 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Brain-Derived Neurotrophic Factor Signaling in Depression and Antidepressant Action
Castrén, E., & Monteggia, L. M. (2021) · Biological Psychiatry · doi:10.1016/j.biopsych.2021.05.008 · Cited by 540 · see citing works
Self-citationKraus, C., Castrén, E., Kasper, S., & Lanzenberger, R. (2017) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2017.03.007 · Cited by 457 · see citing works
Self-citationPage, C. E., & Coutellier, L. (2019) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2019.07.024 · Cited by 213 · see citing works
Riga, D., Kramvis, I., Koskinen, M. K., van Bokhoven, P., van der Harst, J. E., Heistek, T. S., Jaap Timmerman, A., van Nierop, P., van der Schors, R. C., Pieneman, A. W., et al. (2017) · Science Translational Medicine · doi:10.1126/scitranslmed.aai8753 · Cited by 128 · see citing works
Shepard, R., Page, C. E., & Coutellier, L. (2016) · Neuroscience · doi:10.1016/j.neuroscience.2016.06.038 · Cited by 118 · see citing works
iPlasticity: Induced juvenile‐like plasticity in the adult brain as a mechanism of antidepressants
Umemori, J., Winkel, F., Didio, G., Llach Pou, M., & Castrén, E. (2018) · Psychiatry and Clinical Neurosciences · doi:10.1111/pcn.12683 · Cited by 80 · see citing works
Self-citationAutomated analysis of images for molecular quantification in immunohistochemistry
Guirado, R., Carceller, H., Castillo-Gómez, E., Castrén, E., & Nacher, J. (2018) · Heliyon · doi:10.1016/j.heliyon.2018.e00669 · Cited by 63 · see citing works
Self-citationZavvari, F., Nahavandi, A., & Goudarzi, M. (2020) · Journal of Chemical Neuroanatomy · doi:10.1016/j.jchemneu.2019.101711 · Cited by 38 · see citing works
McAvoy, K., Russo, C., Kim, S., Rankin, G., & Sahay, A. (2015) · Hippocampus · doi:10.1002/hipo.22464 · Cited by 36 · see citing works
- Authors
- Guirado, R., Perez-Rando, M., Sanchez-Matarredona, D., Castrén, E., & Nacher, J.
- Affiliations
- Universitat de València (ES)
- ORCID
- Guirado, Ramon
- Venue
- The International Journal of Neuropsychopharmacology
- Publisher
- Oxford University Press (OUP)
- Published
- 2014-04-30
- Volume
- 17
- Issue
- 10
- Pages
- 1635-1646
- ISSN
- 1461-1457 (ISSN-L)
- 1469-5111
- OpenAlex
- W2163584510
- Cited by
- 103
- References
- 45
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 9 · 2023: 7 · 2022: 7 · 2021: 16 · 2020: 12 · 2019: 9 · 2018: 11 · 2017: 12 · 2016: 8 · 2015: 7 · 2014: 1
- FWCI
- 4.26
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The International Journal of Neuropsychopharmacology (publishedVersion)
- PubMed (publishedVersion)
- Työväentutkimus Vuosikirja (submittedVersion, other-oa)
- Funders
- Fundación Alicia Koplowitz
- Ministerio de Economía y Competitividad (FPU12/03200, BFU2012-32512)
- Generalitat Valenciana (BES 2007-15757, PROMETEO2013/069)
- Ministerio de Ciencia e Innovación (BFU2012-32512)
- FP7 Ideas: European Research Council (322742)
- 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, selective serotonin reuptake inhibitors, antidepressant effects, critical period plasticity, cortical interneurons, dendritic spine density, perineuronal nets, parvalbumin interneurons, medial prefrontal cortex, hippocampus, polysialylated NCAM, GAD67, synaptophysin, extracellular matrix
- MeSH terms
- Animals, Cell Count, Cerebral Cortex, Fluoxetine, Gene Expression Regulation, Glutamate Decarboxylase, Hippocampus, Interneurons, Male, Mice, Transgenic, Nerve Net, Nerve Tissue Proteins, Neuronal Plasticity, Parvalbumins, Sialic Acids, Time Factors, Antidepressive Agents, Second-Generation, Neural Cell Adhesion Molecule L1, Dendritic Spines, Green Fluorescent Proteins, Vesicular Glutamate Transport Protein 1, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
