| First Author | Stagni F | Year | 2015 |
| Journal | Neurobiol Dis | Volume | 74 |
| Pages | 204-18 | PubMed ID | 25497735 |
| Mgi Jnum | J:219354 | Mgi Id | MGI:5620552 |
| Doi | 10.1016/j.nbd.2014.12.005 | Citation | Stagni F, et al. (2015) Long-term effects of neonatal treatment with fluoxetine on cognitive performance in Ts65Dn mice. Neurobiol Dis 74:204-18 |
| abstractText | 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 betaCTF peptide in adult Ts65Dn mice were normalized following neonatal treatment with fluoxetine. This effect was accompanied by restoration of endosomal abnormalities, a betaCTF-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. |
