title: Early pharmacotherapy restores neurogenesis and cognitive performance in the Ts65Dn mouse model for Down syndrome.
abstract: 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.
authors.affiliation: Department of Human and General Physiology, University of Bologna, I-40126 Bologna, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Bianchi
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Ciani
authors.forename: Sandra
authors.initials: S
authors.lastname: Guidi
authors.forename: Stefania
authors.initials: S
authors.lastname: Trazzi
authors.forename: Daniela
authors.initials: D
authors.lastname: Felice
authors.forename: Gabriele
authors.initials: G
authors.lastname: Grossi
authors.forename: Mercedes
authors.initials: M
authors.lastname: Fernandez
authors.forename: Alessandro
authors.initials: A
authors.lastname: Giuliani
authors.forename: Laura
authors.initials: L
authors.lastname: Calzà
authors.forename: Renata
authors.initials: R
authors.lastname: Bartesaghi
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000187:drug effects* / Q000503:physiopathology; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D003071:Cognition / Q000187:drug effects*; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000188:drug therapy* / Q000503:physiopathology; D005473:Fluoxetine / Q000008:administration & dosage / Q000494:pharmacology*; D008569:Memory Disorders / Q000188:drug therapy / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D055495:Neurogenesis / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D013234:Stem Cells / Q000187:drug effects / Q000502:physiology; D013997:Time Factors
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D005473:Fluoxetine; D044282:Receptor, Serotonin, 5-HT1A; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors