Fluoxetine induces input-specific hippocampal dendritic spine remodeling along the septotemporal axis in adulthood and middle age
Open accessAbstract
Fluoxetine, a selective serotonin‐reuptake inhibitor (SSRI), is known to induce structural rearrangements and changes in synaptic transmission in hippocampal circuitry. In the adult hippocampus, structural changes include neurogenesis, dendritic, and axonal plasticity of pyramidal and dentate granule neurons, and dedifferentiation of dentate granule neurons. However, much less is known about how chronic fluoxetine affects these processes along the septotemporal axis and during the aging process. Importantly, studies documenting the effects of fluoxetine on density and distribution of spines along different dendritic segments of dentate granule neurons and CA1 pyramidal neurons along the septotemporal axis of hippocampus in adulthood and during aging are conspicuously absent. Here, we use a transgenic mouse line in which mature dentate granule neurons and CA1 pyramidal neurons are genetically labeled with green fluorescent protein (GFP) to investigate the effects of chronic fluoxetine treatment (18 mg/kg/day) on input‐specific spine remodeling and mossy fiber structural plasticity in the dorsal and ventral hippocampus in adulthood and middle age. In addition, we examine levels of adult hippocampal neurogenesis, maturation state of dentate granule neurons, neuronal activity, and glutamic acid decarboxylase‐67 expression in response to chronic fluoxetine in adulthood and middle age. Our studies reveal that while chronic fluoxetine fails to augment adult hippocampal neurogenesis in middle age, the middle‐aged hippocampus retains high sensitivity to changes in the dentate gyrus (DG) such as dematuration, hypoactivation, and increased glutamic acid decarboxylase 67 (GAD67) expression. Interestingly, the middle‐aged hippocampus shows greater sensitivity to fluoxetine‐induced input‐specific synaptic remodeling than the hippocampus in adulthood with the stratum‐oriens of CA1 exhibiting heightened structural plasticity. The input‐specific changes and circuit‐level modifications in middle‐age were associated with modest enhancement in contextual fear memory precision, anxiety‐like behavior and antidepressant‐like behavioral responses. © 2015 Wiley Periodicals, Inc.
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Fluoxetine chronic treatment reduces the number of calbindin+ terminally differentiated neurons.
“However, Encinas et al. (2006) did not detect such a pro-differentiation effect by fluoxetine and, according to Kobayashi et al. (2010), fluoxetine chronic treatment reduces the number of calbindin + terminally differentiated neurons, an effect observed also by McAvoy et al. (2015).”
From Depression and adult neurogenesis: Positive effects of the antidepressant fluoxetine and of physical exercise (2018) · cites this paper as McAvoy et al., 2015
The Results report reduced calbindin expression after four weeks of fluoxetine in specific dentate gyrus regions of adult and middle-aged mice. The Immunohistochemistry methods say calbindin was quantified by labeling intensity, not by counting calbindin-positive neurons, so the claimed reduction in their number was not established. (LLM, conf=0.88)
Experimental — accuracy not yet measuredFluoxetine induced an increase of survival and neurogenesis in 3-month-old mice but not in older mice (6-12 month-old).
“In fact, fluoxetine induced an increase of survival and neurogenesis in 3 monthold mice but not in older mice (6-12 month-old; Couillard-Despres et al., 2009;Li et al., 2015;McAvoy et al., 2015).”
From Depression and adult neurogenesis: Positive effects of the antidepressant fluoxetine and of physical exercise (2018) · cites this paper as McAvoy et al., 2015
The Results report increased progenitor proliferation in adult mice, but not middle-aged mice, after fluoxetine treatment; survival and the number of young adult-born neurons showed only trends toward increases in adults. The study tested 4- and 10-month-old female mice, not 3-month-old mice versus the full 6–12-month age range claimed. (LLM, conf=0.88)
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- Authors
- McAvoy, K., Russo, C., Kim, S., Rankin, G., & Sahay, A.
- Affiliations
- Harvard University (US)
- Corresponding author
- Sahay, Amar
- ORCID
- Sahay, Amar
- Venue
- Hippocampus
- Publisher
- Wiley
- Published
- 2015-05-02
- Volume
- 25
- Issue
- 11
- Pages
- 1429-1446
- ISSN
- 1050-9631 (ISSN-L)
- 1098-1063
- PMC
- PMC4596739
- OpenAlex
- W1956434663
- Cited by
- 36
- References
- 82
- Citations by year
- 2025: 2 · 2024: 1 · 2023: 2 · 2022: 3 · 2021: 2 · 2020: 7 · 2019: 3 · 2018: 5 · 2017: 2 · 2016: 5 · 2015: 4
- FWCI
- 2.48
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Hippocampus (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIMH Biobehavioral Research Awards for Innovative New Scientists (1-R01MH104175)
- Ellison Medical Foundation New Scholar in Aging and a Whitehall Foundation grant (to A.S.)
- Harvard Stem Cell Institute Internship Program (to C.R. and S.K.), Harvard College Research Program funds (to S.K.), and Bennington College Field Work Term Grant (to G.R.)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Keywords
- fluoxetine, selective serotonin reuptake inhibitors, dendritic spine remodeling, septotemporal axis, dentate gyrus granule cells, CA1 pyramidal neurons, adult hippocampal neurogenesis, GAD67, stratum oriens, aging, contextual fear memory, anxiety-like behavior, antidepressant-like behavior, synaptic plasticity
- MeSH terms
- Age Factors, Animals, Female, Fluoxetine, Mice, Inbred C57BL, Mice, Transgenic, Neurons, Selective Serotonin Reuptake Inhibitors, Pyramidal Cells, Dentate Gyrus, Dendritic Spines, Mice, Neurogenesis, CA1 Region, Hippocampal
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