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 hippocampusdependent 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.

Deficiency of Adult Neurogenesis in the Ts65Dn Mouse Model of Down Syndrome

“…It was noted that in prenatal and newborn Ts65Dn mice neurogenesis was significantly reduced (Chakrabarti et al, 2007;Contestabile et al, 2007;Lorenzi & Reeves, 2006). At postnatal day 2 cell proliferation in Ts65Dn mice, assessed 2 hours after single injection of bromodeoxyuridine (BrdU) was significantly reduced (Contestabile et al, 2007); similar results were revealed at postnatal day 15 (Bianchi et al, 2010). However in young adult Ts65Dn mice the results are conflicting (Clark et al, 2006;Rueda et al, 2005).…”

“…Taking to account that this subject is very important for the neurobiology of DS, only a few papers addressed neurogenesis in mouse models of DS (Bianchi et al, 2010;Chakrabarti et al, 2007;Clark et al, 2006;Contestabile et al, 2007;Lorenzi & Reeves, 2006;Rueda et al, 2005). It was noted that in prenatal and newborn Ts65Dn mice neurogenesis was significantly reduced (Chakrabarti et al, 2007;Contestabile et al, 2007;Lorenzi & Reeves, 2006).…”

Down syndrome with asymptomatic neuroglial cyst: A case report and review of the literature

“…After about 4 months, the neurons exhibit enlarged dendrites, but these dendrites stop growing within the first year, and the neurons then appear atrophied compared with neurons in a typical brain at the same age [7]. The expression levels of various neurotrophic factors, including brain-derived neurotrophic factor (BDNF), fall during early development of the brain of patients with DS [10]. BDNF is a neurotrophin that plays a key role in neurogenesis and the maintenance of neuronal plasticity by binding specifically to tropomyosin-related kinase receptor B [11].…”

Effects of vitamin C on inhalation anesthetic isoflurane-induced developmental, neuronal apoptosis in neonatal rats

“…It is widely believed that neurogenesis enables hippocampal plasticity and new memories (Denis-Donini et al, 2008). In addition to neuronal apoptosis, several recent studies correlate alterations in neurogenesis with cognitive performance (Zhao et al, 2008;Bianchi et al, 2010).…”