Defects in embryonic neurogenesis and initial synapse formation in the forebrain of the Ts65Dn mouse model of Down syndrome.
Trisomy 21, one of the most prevalent congenital birth defects, results in a constellation of phenotypes collectively termed Down syndrome (DS). Mental retardation and motor and sensory deficits are among the many debilitating symptoms of DS. Alterations in brain growth and synaptic development are thought to underlie the cognitive impairments in DS, but the role of early brain development has not been studied because of the lack of embryonic human tissue and because of breeding difficulties in mouse models of DS. We generated a breeding colony of the Ts65Dn mouse model of DS to test the hypothesis that early defects in embryonic brain development are a component of brain dysfunction in DS. We found substantial delays in prenatal growth of the Ts65Dn cerebral cortex and hippocampus because of longer cell cycle duration and reduced neurogenesis from the ventricular zone neural precursor population. In addition, the Ts65Dn neocortex remains hypocellular after birth and there is a lasting decrease in synaptic development beginning in the first postnatal week. These results demonstrate that specific abnormalities in embryonic forebrain precursor cells precede early deficits in synaptogenesis and may underlie the postnatal disabilities in Ts65Dn and DS. The early prenatal period is therefore an important new window for possible therapeutic amelioration of the cognitive symptoms in DS.
Chakrabarti
Lina
L
Center for Neuroscience Research, Children's National Medical Center, Washington, DC 20010, USA.
Galdzicki
Zygmunt
Z
Haydar
Tarik F
TF
D000818:Animals; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000196:embryology* / Q000473:pathology; D047108:Embryonic Development / Q000502:physiology; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000166:cytology / Q000473:pathology; D016548:Prosencephalon / Q000196:embryology* / Q000473:pathology; D013569:Synapses / Q000473:pathology