Prenatal pharmacotherapy rescues brain development in a Down's syndrome mouse model

Guidi, Sandra, Stagni, Fiorenza, Bianchi, Patrizia, Ciani, Elisabetta, Giacomini, Andrea, De Franceschi, Marianna, Moldrich, Randal, Kurniawan, Nyoman, Mardon, Karine, Giuliani, Alessandro, Calzà, Laura and Bartesaghi, Renata (2014) Prenatal pharmacotherapy rescues brain development in a Down's syndrome mouse model. Brain, 137 2: 380-401. doi:10.1093/brain/awt340

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Author Guidi, Sandra
Stagni, Fiorenza
Bianchi, Patrizia
Ciani, Elisabetta
Giacomini, Andrea
De Franceschi, Marianna
Moldrich, Randal
Kurniawan, Nyoman
Mardon, Karine
Giuliani, Alessandro
Calzà, Laura
Bartesaghi, Renata
Title Prenatal pharmacotherapy rescues brain development in a Down's syndrome mouse model
Journal name Brain   Check publisher's open access policy
ISSN 0006-8950
1460-2156
Publication date 2014-02-01
Year available 2013
Sub-type Article (original research)
DOI 10.1093/brain/awt340
Open Access Status DOI
Volume 137
Issue 2
Start page 380
End page 401
Total pages 22
Place of publication Oxford, United Kingdom
Publisher Oxford University Press
Language eng
Subject 2700 Medicine
1201 Arts and Humanities (miscellaneous)
2728 Clinical Neurology
Abstract 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.
Formatted abstract
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.
Keyword Down’s syndrome
Brain development
Intellectual disability
Neurogenesis impairment
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Published online 12 December 2013

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2014 Collection
Centre for Advanced Imaging Publications
 
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Created: Thu, 09 Jan 2014, 01:20:08 EST by Sandrine Ducrot on behalf of Centre for Advanced Imaging