Intellectual impairment is a strongly disabling feature of
Down's syndrome, a
genetic disorder of high prevalence (1 in 700-1000 live births) caused by
trisomy of chromosome 21. Accumulating evidence shows that widespread neurogenesis impairment is a major determinant of abnormal brain development and, hence, of
intellectual disability in
Down's syndrome. This defect is worsened by dendritic hypotrophy and connectivity alterations. Most of the
pharmacotherapies designed to improve cognitive performance in
Down's syndrome have been attempted in
Down's syndrome mouse models during adult life stages. Yet, as neurogenesis is mainly a prenatal event, treatments aimed at correcting neurogenesis failure in
Down's syndrome should be administered during pregnancy. Correction of neurogenesis during the very first stages of brain formation may, in turn, rescue improper brain wiring. The aim of our study was to establish whether it is possible to rescue the neurodevelopmental alterations that characterize the trisomic brain with a prenatal
pharmacotherapy with
fluoxetine, a
drug that is able to restore post-natal hippocampal neurogenesis in the Ts65Dn mouse model of
Down's syndrome. Pregnant Ts65Dn females were treated with
fluoxetine from embryonic Day 10 until delivery. On post-natal Day 2 the pups received an injection of 5-bromo-2-deoxyuridine and were sacrificed after either 2 h or after 43 days (at the age of 45 days). Untreated 2-day-old Ts65Dn mice exhibited a severe neurogenesis reduction and hypocellularity throughout the forebrain (subventricular zone, subgranular zone, neocortex, striatum, thalamus and hypothalamus), midbrain (mesencephalon) and hindbrain (cerebellum and pons). In embryonically treated 2-day-old Ts65Dn mice, precursor proliferation and cellularity were fully restored throughout all brain regions. The recovery of proliferation potency and cellularity was still present in treated Ts65Dn 45-day-old mice. Moreover, embryonic treatment restored dendritic development, cortical and hippocampal synapse development and brain volume. Importantly, these effects were accompanied by recovery of behavioural performance. The cognitive deficits caused by
Down's syndrome have long been considered irreversible. The current study provides novel evidence that a
pharmacotherapy with
fluoxetine during embryonic development is able to fully rescue the abnormal brain development and behavioural deficits that are typical of
Down's syndrome. If the positive effects of
fluoxetine on the brain of a mouse model are replicated in foetuses with
Down's syndrome,
fluoxetine, a
drug usable in humans, may represent a breakthrough for the
therapy of
intellectual disability in
Down's syndrome.