Combination of fluoxetine and extinction treatments forms a unique synaptic protein profile that correlates with long-term fear reduction in adult mice
Open accessAbstract
The antidepressant fluoxetine induces synaptic plasticity in the visual and fear networks and promotes the structural remodeling of neuronal circuits, which is critical for experience-dependent plasticity in response to an environmental stimulus. We recently demonstrated that chronic fluoxetine administration together with extinction training in adult mice reduced fear in a context-independent manner. Fear conditioning and extinction alter excitatory and inhibitory transmissions within the fear circuitry. In this study, we investigated whether fluoxetine, extinction or their combination produced distinct long-lasting changes in the synaptic protein profile in the amygdala, hippocampus and prefrontal cortex of conditioned mice. We determined that extinction induced synaptophysin expression and down-regulated the GluA1:GluA2 ratio throughout the fear network in water- and fluoxetine-treated mice, suggesting a common fluoxetine-independent mechanism for increased synaptic transmission and re-arrangement of AMPA-receptors by extinction training. In contrast to common changes, the presynaptic vesicular neurotransmitter transporters VGAT and Vglut1 were upregulated after extinction in water- and fluoxetine-treated mice, respectively. The cortical levels of the GABA transporter Gat1 were reduced in high-freezing water-drinking mice, suggesting a maladaptive increase of GABA spillover at cortical inhibitory synapses. Fear conditioning decreased, and extinction induced the expression of GABA-receptor alpha1 and alpha2 subunits in water- and fluoxetine-treated mice, respectively. Only a combination of fluoxetine with extinction enhanced GluN2A expression in the amygdala and hippocampus, emphasizing the role of this NMDA-receptor subunit in the successful erasure of fear memories. Our finding provides novel data that may become helpful in developing beneficial pharmacological fear-reducing treatment strategies.
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?
Experiences leave lasting marks on gene expression by altering chromatin structure and DNA methylation epigenetically.
“Experiences have long-lasting effects on gene expression through the epigenetic regulation of chromatin structure and DNA methylation203,204.”
From Neuronal plasticity and neurotrophic factors in drug responses (2017) · cites this paper as [203]
Several drugs used clinically act as HDAC inhibitors.
“several drugs in clinical use act as HDAC inhibitors203.”
From Neuronal plasticity and neurotrophic factors in drug responses (2017) · cites this paper as [203]
Histone acetylation can be increased by HDAC inhibitors.
“Histone acetylation can be increased by inhibitors of histone deacetylase (HDAC)”
From Neuronal plasticity and neurotrophic factors in drug responses (2017) · cites this paper as [203]
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
Neural Mechanisms of Extinction Learning and Retrieval
Quirk, G. J., & Mueller, D. (2008) · Neuropsychopharmacology · doi:10.1038/sj.npp.1301555 · Cited by 1,645 · see citing works
Genetic variant BDNF (Val66Met) polymorphism alters anxiety-related behavior
Chen, Z.-Y., Jing, D., Bath, K. G., Ieraci, A., Khan, T., Siao, C.-J., Herrera, D. G., Toth, M., Yang, C., McEwen, B. S., et al. (2006) · Science · doi:10.1126/science.1129663 · Cited by 1,340 · see citing works
Myers, K. M., & Davis, M. (2007) · Molecular Psychiatry · doi:10.1038/sj.mp.4001939 · Cited by 1,277 · see citing works
Fritschy, J., & Mohler, H. (1995) · Journal of Comparative Neurology · doi:10.1002/cne.903590111 · Cited by 1,244 · see citing works
Patterson, S. L., Abel, T., Deuel, T. A. S., Martin, K. C., Rose, J. C., & Kandel, E. R. (1996) · Neuron · doi:10.1016/s0896-6273(00)80140-3 · Cited by 1,233 · see citing works
The GABAergic deficit hypothesis of major depressive disorder
Luscher, B., Shen, Q., & Sahir, N. (2011) · Molecular Psychiatry · doi:10.1038/mp.2010.120 · Cited by 934 · see citing works
Amygdala inhibitory circuits and the control of fear memory
Ehrlich, I., Humeau, Y., Grenier, F., Ciocchi, S., Herry, C., & Lüthi, A. (2009) · Neuron · doi:10.1016/j.neuron.2009.05.026 · Cited by 878 · see citing works
Walker, D. L., Ressler, K. J., Lu, K.-T., & Davis, M. (2002) · The Journal of Neuroscience · doi:10.1523/jneurosci.22-06-02343.2002 · Cited by 815 · see citing works
Heldt, S. A., Stanek, L., Chhatwal, J. P., & Ressler, K. J. (2007) · Molecular Psychiatry · doi:10.1038/sj.mp.4001957 · Cited by 684 · see citing works
Effects of Chronic Fluoxetine in Animal Models of Anxiety and Depression
Dulawa, S. C., Holick, K. A., Gundersen, B., & Hen, R. (2004) · Neuropsychopharmacology · doi:10.1038/sj.npp.1300433 · Cited by 671 · see citing works
Mahan, A. L., & Ressler, K. J. (2011) · Trends in Neurosciences · doi:10.1016/j.tins.2011.06.007 · Cited by 616 · see citing works
A Genetic Variant BDNF Polymorphism Alters Extinction Learning in Both Mouse and Human
Soliman, F., Glatt, C. E., Bath, K. G., Levita, L., Jones, R. M., Pattwell, S. S., Jing, D., Tottenham, N., Amso, D., Somerville, L. H., et al. (2010) · Science · doi:10.1126/science.1181886 · Cited by 585 · see citing works
Wojcik, S. M., Rhee, J. S., Herzog, É., Sigler, A., Jahn, R., Takamori, S., Brose, N., & Rosenmund, C. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0401764101 · Cited by 510 · see citing works
Calcium-Permeable AMPA Receptor Dynamics Mediate Fear Memory Erasure
Clem, R. L., & Huganir, R. L. (2010) · Science · doi:10.1126/science.1195298 · Cited by 496 · see citing works
ΔFosB in brain reward circuits mediates resilience to stress and antidepressant responses
Vialou, V., Robison, A. J., LaPlant, Q. C., Covington, H. E., Dietz, D. M., Ohnishi, Y. N., Mouzon, E., Rush, A. J., Watts, E. L., Wallace, D. L., et al. (2010) · Nature Neuroscience · doi:10.1038/nn.2551 · Cited by 479 · see citing works
Induction of Fear Extinction with Hippocampal-Infralimbic BDNF
Peters, J., Dieppa-Perea, L. M., Melendez, L. M., & Quirk, G. J. (2010) · Science · doi:10.1126/science.1186909 · Cited by 462 · 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-citationA shared vesicular carrier allows synaptic corelease of GABA and glycine
Wojcik, S. M., Katsurabayashi, S., Guillemin, I., Friauf, E., Rosenmund, C., Brose, N., & Rhee, J.-S. (2006) · Neuron · doi:10.1016/j.neuron.2006.04.016 · Cited by 374 · see citing works
Santini, E., Muller, R. U., & Quirk, G. J. (2001) · The Journal of Neuroscience · doi:10.1523/jneurosci.21-22-09009.2001 · Cited by 358 · see citing works
Rantamäki, T., Hendolin, P., Kankaanpää, A., Mijatovic, J., Piepponen, P., Domenici, E., Chao, M. V., Männistö, P. T., & Castrén, E. (2007) · Neuropsychopharmacology · doi:10.1038/sj.npp.1301345 · Cited by 305 · see citing works
Self-citationVolk, D. W. (2002) · Cerebral Cortex · doi:10.1093/cercor/12.10.1063 · Cited by 264 · see citing works
Amygdala depotentiation and fear extinction
Kim, J., Lee, S., Park, K., Hong, I., Song, B., Son, G. H., Park, H., Kim, W. R., Park, E. J., Choe, H. K., et al. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0710548105 · Cited by 252 · see citing works
Amygdala BDNF signaling is required for consolidation but not encoding of extinction
Chhatwal, J. P., Rattiner, L. M., Davis, M., & Ressler, K. J. (2006) · Nature Neuroscience · doi:10.1038/nn1718 · Cited by 243 · see citing works
Erasing Fear Memories with Extinction Training: Figure 1.
Quirk, G. J., Paré, D., Richardson, R., Herry, C., Monfils, M., Schiller, D., & Vicentic, A. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.4268-10.2010 · Cited by 220 · see citing works
Chiaruttini, C., Vicario, A., Li, Z., Baj, G., Braiuca, P., Wu, Y., Lee, F. S., Gardossi, L., Baraban, J. M., & Tongiorgi, E. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0902833106 · Cited by 217 · 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
Chhatwal, J. P., Myers, K. M., Ressler, K. J., & Davis, M. E. (2005) · Journal of Neuroscience · doi:10.1523/jneurosci.3301-04.2005 · Cited by 214 · see citing works
Selective serotonin reuptake inhibitors in affective disorders — I. Basic pharmacology
Goodnick, P. J., & Goldstein, B. J. (1998) · Journal of Psychopharmacology · doi:10.1177/0269881198012003021 · Cited by 181 · see citing works
Tordera, R. M., Totterdell, S., Wojcik, S. M., Brose, N., Elizalde, N., Lasheras, B., & del Rı́o, J. A. (2007) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2006.05259.x · Cited by 169 · see citing works
Damme, P. V., Bosch, L. V. D., Houtte, E. V., Callewaert, G., & Robberecht, W. (2002) · Journal of Neurophysiology · doi:10.1152/jn.2002.88.3.1279 · Cited by 145 · see citing works
Karpova, N. N., Lindholm, J., Pruunsild, P., Timmusk, T., & Ċastrén, E. (2008) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2008.09.002 · Cited by 142 · see citing works
Self-citationSchoenfeld, T. J., Rada, P., Pieruzzini, P. R., Hsueh, B., & Gould, E. (2013) · The Journal of Neuroscience · doi:10.1523/jneurosci.5352-12.2013 · Cited by 138 · see citing works
Anxioselective Compounds Acting at the GABAA Receptor Benzodiazepine Binding Site
Atack, J. R. (2003) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/1568007033482841 · Cited by 130 · see citing works
Heldt, S. A., & Ressler, K. J. (2007) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2007.05970.x · Cited by 125 · see citing works
Balschun, D., Moechars, D., Callaerts‐Vegh, Z., Vermaercke, B., Acker, N. V., Andries, L. J., & D’Hooge, R. (2009) · Cerebral Cortex · doi:10.1093/cercor/bhp133 · Cited by 123 · see citing works
Mao, S.-C., Hsiao, Y., & Gean, P. (2006) · Journal of Neuroscience · doi:10.1523/jneurosci.0365-06.2006 · Cited by 112 · see citing works
Guastella, A. J., Lovibond, P. F., Dadds, M. R., Mitchell, P., & Richardson, R. (2007) · Behaviour Research and Therapy · doi:10.1016/j.brat.2006.07.005 · Cited by 106 · see citing works
Camp, M., MacPherson, K. P., Lederle, L. I., Graybeal, C., Gaburro, S., DeBrouse, L., Ihne, J. L., Bravo, J. A., O’Connor, R. M., Ciocchi, S., et al. (2012) · Neuropsychopharmacology · doi:10.1038/npp.2011.340 · Cited by 101 · see citing works
Smith, K. S., Engin, E., Meloni, E. G., & Rudolph, U. (2012) · Neuropharmacology · doi:10.1016/j.neuropharm.2012.03.001 · Cited by 94 · see citing works
Eyre, M. D., Renzi, M., Farrant, M., & Nusser, Z. (2012) · Journal of Neuroscience · doi:10.1523/jneurosci.6495-11.2012 · Cited by 90 · see citing works
Chronic Antidepressant Treatment Impairs the Acquisition of Fear Extinction
Burghardt, N. S., Sigurdsson, T., Gorman, J. M., McEwen, B. S., & LeDoux, J. E. (2012) · Biological Psychiatry · doi:10.1016/j.biopsych.2012.10.012 · Cited by 88 · see citing works
Hong, I., Song, B., Lee, S., Kim, J., Kim, J., & Choi, S. (2009) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2009.07004.x · Cited by 79 · see citing works
Lin, H., Mao, S.-C., & Gean, P. (2009) · Biological Psychiatry · doi:10.1016/j.biopsych.2009.04.003 · Cited by 66 · see citing works
Melo, C. V., Mele, M., Curcio, M., Comprido, D., Silva, C. G., & Duarte, C. B. (2013) · PLoS ONE · doi:10.1371/journal.pone.0053793 · Cited by 63 · see citing works
Chronic treatment with fluoxetine prevents the return of extinguished auditory-cued conditioned fear
Deschaux, O., Spennato, G., Moreau, J., & Garcia, R. (2010) · Psychopharmacology · doi:10.1007/s00213-010-2134-y · Cited by 57 · see citing works
Vlachos, I., Herry, C., Lüthi, A., Aertsen, A., & Kumar, A. (2011) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1001104 · Cited by 56 · see citing works
Long-Lasting Hippocampal Synaptic Protein Loss in a Mouse Model of Posttraumatic Stress Disorder
Herrmann, L., Ionescu, I. A., Henes, K., Golub, Y., Wang, N. X. R., Buell, D. R., Holsboer, F., Wotjak, C. T., & Schmidt, U. (2012) · PLoS ONE · doi:10.1371/journal.pone.0042603 · Cited by 50 · see citing works
Physical dependence on benzodiazepines: differences within the class
Wolf, B., & Griffiths, R. R. (1991) · Drug and Alcohol Dependence · doi:10.1016/0376-8716(91)90044-y · Cited by 49 · see citing works
Lange, M. D., Doengi, M., Lesting, J., Pape, H., & Jüngling, K. (2011) · The Journal of Physiology · doi:10.1113/jphysiol.2011.221317 · Cited by 49 · see citing works
González‐Burgos, G., Rotaru, D. C., Zaitsev, A. V., Povysheva, N. V., & Lewis, D. A. (2008) · Journal of Neurophysiology · doi:10.1152/jn.91161.2008 · Cited by 47 · see citing works
Otto, M. W., Bruce, S. E., & Deckersbach, T. (2005) · PubMed · Cited by 41 · see citing works
Pereira, M. E., Rosat, R. M., Huang, C. H., Godoy, M. G., & al, E. (1989) · Behavioral Neuroscience · doi:10.1037//0735-7044.103.1.202 · Cited by 37 · see citing works
Lin, H., Mao, S.-C., Su, C.-L., & Gean, P. (2009) · The International Journal of Neuropsychopharmacology · doi:10.1017/s1461145709990678 · Cited by 34 · see citing works
Contextual control over the expression of fear in rats conditioned under a benzodiazepine
Harris, J., & Westbrook, F. (2001) · Psychopharmacology · doi:10.1007/s002130100757 · Cited by 33 · see citing works
Pereira, M. E., Rosat, R. M., Huang, C. H., et al. (1989) · Behavioral Neuroscience · doi:10.1037/0735-7044.103.1.202 · Cited by 32 · see citing works
Vesicular GABA transporter ( VGAT ) transports β‐alanine
Juge, N., Omote, H., & Moriyama, Y. (2013) · Journal of Neurochemistry · doi:10.1111/jnc.12393 · Cited by 29 · see citing works
Koester, C., Rudolph, U., Haenggi, T., Papilloud, A., Fritschy, J., & Crestani, F. (2012) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2012.10.004 · Cited by 20 · see citing works
Xue, L., Li, Z., Chen, Z.-X., Wang, X., Shi, Y.-W., & Zhao, H. (2014) · Neuroscience · doi:10.1016/j.neuroscience.2013.12.014 · Cited by 11 · see citing works
Nemeroff (1998) · doi:10.1002/(sici)1520-6394(1998)8:1+
Flagged first, then by citations
Cited by
Sorted by citations
Singewald, N., Schmuckermair, C., Whittle, N., Holmes, A., & Ressler, K. J. (2015) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2014.12.004 · Cited by 390 · see citing works
Neuronal plasticity and neurotrophic factors in drug responses
Castrén, E., & Antila, H. (2017) · Molecular Psychiatry · doi:10.1038/mp.2017.61 · Cited by 284 · see citing works
Self-citationNeurobiology of fear and specific phobias
Garcia, R. (2017) · Learning & Memory · doi:10.1101/lm.044115.116 · Cited by 239 · see citing works
Rief, W., Barsky, A. J., Bingel, U., Doering, B. K., Schwarting, R., Wöhr, M., & Schweiger, U. (2016) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2015.11.008 · Cited by 67 · see citing works
Diniz, C. R. A. F., Casarotto, P. C., Resstel, L., & Joca, S. R. L. (2018) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2018.04.001 · Cited by 58 · see citing works
A precision medicine approach to pharmacological adjuncts to extinction: A call to broaden research
King, G., Baker, K. D., Bisby, M. A., Chan, D., Cowan, C. S. M., Stylianakis, A. A., Zimmermann, K. S., & Richardson, R. (2019) · Psychopharmacology · doi:10.1007/s00213-018-4999-0 · Cited by 6 · see citing works
- Authors
- Popova, D., Ágústsdóttir, A., Lindholm, J., Mazulis, U., Akamine, Y., Castrén, E., & Karpova, N. N.
- Affiliations
- University of Helsinki (FI)
- Corresponding author
- Karpova, Nina N.
- Venue
- European Neuropsychopharmacology
- Publisher
- Elsevier BV
- Published
- 2014-07
- Volume
- 24
- Issue
- 7
- Pages
- 1162-1174
- ISSN
- 0924-977X (ISSN-L)
- OpenAlex
- W2009366565
- Cited by
- 26
- References
- 59
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 4 · 2023: 1 · 2022: 2 · 2021: 1 · 2020: 2 · 2018: 3 · 2017: 3 · 2016: 3 · 2015: 2 · 2014: 2
- FWCI
- 1.86
- Type
- journal article
- Language
- en
- Open access
- green
- hdl.handle.net
- Licence
- Locations
- European Neuropsychopharmacology (publishedVersion)
- PubMed (publishedVersion)
- Työväentutkimus Vuosikirja (submittedVersion, other-oa)
- Funders
- Kansainvälisen Liikkuvuuden ja Yhteistyön Keskus
- Sigrid Juséliuksen Säätiö
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- fluoxetine, fear extinction, fear conditioning, synaptic plasticity, synaptophysin, glutamate transporters, GABA transporters, fear memory, amygdala, hippocampus, prefrontal cortex, antidepressant combination therapy
- MeSH terms
- Animals, Conditioning, Classical, Extinction, Psychological, Fear, Fluoxetine, Hippocampus, Neuronal Plasticity, Synapses, Synaptophysin, Selective Serotonin Reuptake Inhibitors, Receptors, AMPA, Protein Subunits, 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
