title: Long-term effects of neonatal treatment with fluoxetine on cognitive performance in Ts65Dn mice.
abstract: Individuals with Down syndrome (DS), a genetic condition caused by triplication of chromosome 21, are characterized by intellectual disability and are prone to develop Alzheimer's disease (AD), due to triplication of the amyloid precursor protein (APP) gene. Recent evidence in the Ts65Dn mouse model of DS shows that enhancement of serotonergic transmission with fluoxetine during the perinatal period rescues neurogenesis, dendritic pathology and behavior, indicating that cognitive impairment can be pharmacologically restored. A crucial question is whether the short-term effects of early treatments with fluoxetine disappear at adult life stages. In the current study we found that hippocampal neurogenesis, dendritic pathology and hippocampus/amygdala-dependent memory remained in their restored state when Ts65Dn mice, which had been neonatally treated with fluoxetine, reached adulthood. Additionally, we found that the increased levels of the APP-derived βCTF peptide in adult Ts65Dn mice were normalized following neonatal treatment with fluoxetine. This effect was accompanied by restoration of endosomal abnormalities, a βCTF-dependent feature of DS and AD. While untreated adult Ts65Dn mice had reduced hippocampal levels of the 5-HT1A receptor (5-HT1A-R) and methyl-CpG-binding protein (MeCP2), a protein that promotes 5-HT1A-R transcription, in neonatally-treated mice both 5-HT1A-R and MeCP2 were normalized. In view of the crucial role of serotonin in brain development, these findings suggest that the enduring outcome of neonatal treatment with fluoxetine may be due to MeCP2-dependent restoration of the 5-HT1A-R. Taken together, results provide new hope for the therapy of DS, showing that early treatment with fluoxetine enduringly restores cognitive impairment and prevents early signs of AD-like pathology.
authors.affiliation: Department of Biomedical and Neuromotor Sciences, University of Bologna, Italy.
authors.forename: Fiorenza
authors.initials: F
authors.lastname: Stagni
authors.affiliation: Department of Biomedical and Neuromotor Sciences, University of Bologna, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Giacomini
authors.affiliation: Department of Biomedical and Neuromotor Sciences, University of Bologna, Italy.
authors.forename: Sandra
authors.initials: S
authors.lastname: Guidi
authors.affiliation: Department of Biomedical and Neuromotor Sciences, University of Bologna, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Ciani
authors.affiliation: Department of Biomedical and Neuromotor Sciences, University of Bologna, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Ragazzi
authors.affiliation: Centralized Laboratory, S. Orsola-Malpighi University Hospital, Bologna, Italy.
authors.forename: Mirco
authors.initials: M
authors.lastname: Filonzi
authors.affiliation: Centralized Laboratory, S. Orsola-Malpighi University Hospital, Bologna, Italy.
authors.forename: Rosaria
authors.initials: R
authors.lastname: De Iasio
authors.affiliation: Department of Medical and Surgical Sciences, University of Bologna, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Rimondini
authors.affiliation: Department of Biomedical and Neuromotor Sciences, University of Bologna, Italy. Electronic address: renata.bartesaghi@unibo.it.
authors.forename: Renata
authors.initials: R
authors.lastname: Bartesaghi
mesh_terms: D000544:Alzheimer Disease / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D000818:Animals; D000831:Animals, Newborn; D003071:Cognition / Q000187:drug effects* / Q000502:physiology; D003712:Dendrites / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology / Q000523:psychology; D011992:Endosomes / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D005260:Female; D005473:Fluoxetine / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000378:metabolism; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058953:Neural Stem Cells / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D055495:Neurogenesis / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018697:Nootropic Agents / Q000494:pharmacology*; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism
chemical_list: C497394:Mecp2 protein, rat; D051783:Methyl-CpG-Binding Protein 2; D018696:Neuroprotective Agents; D018697:Nootropic Agents; D005473:Fluoxetine; D044282:Receptor, Serotonin, 5-HT1A
keywords: 5-HT1A receptor; Alzheimer's disease; Cognitive impairment; Down syndrome; Pharmacotherapy