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Early Pharmacotherapy Restores Neurogenesis and Cognitive Performance in the Ts65Dn Mouse Model for Down Syndrome
Open accessAbstract
Down syndrome (DS) is a genetic pathology characterized by intellectual disability and brain hypotrophy. Widespread neurogenesis impairment characterizes the fetal and neonatal DS brain, strongly suggesting that this defect may be a major determinant of mental retardation. Our goal was to establish, in a mouse model for DS, whether early pharmacotherapy improves neurogenesis and cognitive behavior. Neonate Ts65Dn mice were treated from postnatal day (P) 3 to P15 with fluoxetine, an antidepressant that inhibits serotonin (5-HT) reuptake and increases proliferation in the adult Ts65Dn mouse (Clark et al., 2006). On P15, they received a BrdU injection and were killed after either 2 h or 1 month. Results showed that P15 Ts65Dn mice had notably defective proliferation in the hippocampal dentate gyrus, subventricular zone, striatum, and neocortex and that proliferation was completely rescued by fluoxetine. In the hippocampus of untreated P15 Ts65Dn mice, we found normal 5-HT levels but a lower expression of 5-HT1A receptors and brain-derived neurotrophic factor (BDNF). In Ts65Dn mice, fluoxetine treatment restored the expression of 5-HT1A receptors and BDNF. One month after cessation of treatment, there were more surviving cells in the dentate gyrus of Ts65Dn mice, more cells with a neuronal phenotype, more proliferating precursors, and more granule cells. These animals were tested for contextual fear conditioning, a hippocampus-dependent memory task, and exhibited a complete recovery of memory performance. Results show that early pharmacotherapy with a drug usable by humans can correct neurogenesis and behavioral impairment in a model for DS.
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“Ts65Dn mice do exhibit deficient neurological structural phenotypes in brain regions where we found DYRK1A overexpression including during perinatal or early postnatal ages (Baxter et al., 2000; Belichenko et al., 2004; Bianchi et al., 2010; Chakrabarti et al., 2007; Roper et al., 2006b; Stagni et al., 2016).”
From Sex-specific developmental alterations in DYRK1A expression in the brain of a Down syndrome mouse model (2024) · cites this paper as Bianchi et al., 2010
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Metadata
- Authors
- Bianchi, P., Ciani, E., Guidi, S., Trazzi, S., Felice, D., Grossi, G., Fernandez, M., Giuliani, A., Calza, L., & Bartesaghi, R.
- Affiliations
- University of Bologna (IT)
- IRCCS Azienda Ospedliero-Universitaria di Bologna Policlinico di Sant'Orsola (IT)
- Corresponding author
- Bartesaghi, R.
- Venue
- Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2010-06-30
- Volume
- 30
- Issue
- 26
- Pages
- 8769-8779
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6632890
- OpenAlex
- W2086398583
- Cited by
- 188
- References
- 62
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 11 · 2023: 5 · 2022: 8 · 2021: 8 · 2020: 7 · 2019: 13 · 2018: 9 · 2017: 20 · 2016: 10 · 2015: 11 · 2014: 21 · 2013: 16 · 2012: 25
- FWCI
- 17.18
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion)
- Institutional Research Information System University of Ferrara (University of Ferrara) (submittedVersion)
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- Down syndrome, Ts65Dn mouse model, fluoxetine, neurogenesis, serotonin, 5-HT1A receptor, brain-derived neurotrophic factor, dentate gyrus, subventricular zone, striatum, neocortex, cell proliferation, contextual fear conditioning, hippocampal-dependent memory, intellectual disability
- MeSH terms
- Animals, Animals, Newborn, Brain, Cognition, Disease Models, Animal, Down Syndrome, Fluoxetine, Memory Disorders, Mice, Transgenic, Neurons, Serotonin, Stem Cells, Time Factors, Selective Serotonin Reuptake Inhibitors, Brain-Derived Neurotrophic Factor, Receptor, Serotonin, 5-HT1A, Cell Proliferation, Mice, Neurogenesis
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