Down syndrome (DS) is the most common genetic form of mental retardation. One of the specific hallmarks of DS is anomalous cerebral cortical development. Studies have found cortical hypoplasia, abnormal lamination, reduced synaptogenesis, aberrant dendritic development, and a delay in myelination. These abnormalities lead to abnormal cortical organization and circuitry. Because of the lack of adequate DS tissue, it has been difficult to determine when abnormalities in cortical development first occur. Newer methods of brain imaging especially MRI have allowed studies of brain development to be done 3-dimensionally, without the invasiveness of histological methods. The present experiments will investigate development of the cortex during fetal development in DS compared to normal human development and also compare cortical formation and growth in DS with an animal model of DS, the segmental trisomy 16 mice (Ts65Dn). Many of the same chromosome 21 genes triplicated in DS are also triplicated in Ts65Dn and therefore Ts65Dn and DS share a common genetic abnormality. Using high resolution NM and the new method of resolving water diffusion in situ, diffusion tensor imaging (DTI) fiber bundle architecture and cortical organization will be resolved. We will characterize the volume of cortical regions, delineate the microstructure of the cortex and the architecture of major fiber bundles present during the fetal period. We have a unique collection of postmortem fetal DS brains (18-26 weeks gestation), a period of formation of future cortical organization. We will directly address the hypothesis that cortical volume and the size and shape of specific fiber bundles is abnormal in DS.
In Aim 1, we will characterize the volume of cortical regions in fetal DS and Ts65Dn using MRI.
In Aim 2, we will characterize cortical microstructure and fiber bundle architecture in DS and Ts65Dn using DTI. Thus we will not only characterize fetal development in DS and Ts65Dn, but also determine how similar they are. Defects during fetal neocortical development could lead to permanent cortical abnormalities responsible for cognitive deficits.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21NS044151-02
Application #
6658991
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Babcock, Debra J
Project Start
2002-09-15
Project End
2005-08-31
Budget Start
2003-09-01
Budget End
2004-08-31
Support Year
2
Fiscal Year
2003
Total Cost
$184,012
Indirect Cost
Name
University of Maryland Baltimore
Department
Pharmacology
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Clark, Sarah; Schwalbe, Jennifer; Stasko, Melissa R et al. (2006) Fluoxetine rescues deficient neurogenesis in hippocampus of the Ts65Dn mouse model for Down syndrome. Exp Neurol 200:256-61
Bambrick, Linda L; Yarowsky, Paul J; Krueger, Bruce K (2003) Altered astrocyte calcium homeostasis and proliferation in theTs65Dn mouse, a model of Down syndrome. J Neurosci Res 73:89-94