Down syndrome (DS, trisomy 21) is the most common genetic cause of intellectual disability but the neuroanatomical abnormalities that contribute to specific cognitive deficits have not been well defined. Histopathological observations have consistently implicated reduced interneuron number as a major defect in the DS cerebral cortex. Mouse and human data indicate that interneuron development is faulty in DS and warrant further investigation in human. To better understand how mistakes in interneuron development may underlie intellectual disability in DS, we propose to test the hypothesis that the development of human trisomy 21 (Ts21) interneuron progenitors is impaired. We will develop an in vitro paradigm that uses human induced pluripotent stem cells to model both spatial and temporal aspects of human interneuron progenitor development. Using this system, we will determine whether Ts21 iPSC-derived interneuron progenitors have defects in interneuron generation that may lead to the generation of fewer interneurons in DS brain.

Public Health Relevance

As the most common genetic developmental disorder that leads to mental retardation, Down syndrome is a public health concern. The proposed research will better define the developmental defects that occur during formation of the human brain in Down syndrome. The results will provide insight into the biological bases of intellectual and developmental disabilities and could potentially lead to the design of therapeutic interventions.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21HD085288-01
Application #
8953585
Study Section
Neurogenesis and Cell Fate Study Section (NCF)
Program Officer
Parisi, Melissa, MD, Phd
Project Start
2015-09-05
Project End
2017-08-31
Budget Start
2015-09-05
Budget End
2016-08-31
Support Year
1
Fiscal Year
2015
Total Cost
$191,250
Indirect Cost
$66,250
Name
University of Wisconsin Madison
Department
Pediatrics
Type
Other Domestic Higher Education
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
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Li, Meng; Zhao, Huashan; Ananiev, Gene E et al. (2017) Establishment of Reporter Lines for Detecting Fragile X Mental Retardation (FMR1) Gene Reactivation in Human Neural Cells. Stem Cells 35:158-169
Weick, Jason P; Kang, Huining; Bonadurer 3rd, George F et al. (2016) Gene Expression Studies on Human Trisomy 21 iPSCs and Neurons: Towards Mechanisms Underlying Down's Syndrome and Early Alzheimer's Disease-Like Pathologies. Methods Mol Biol 1303:247-65
Bhattacharyya, Anita; Zhao, Xinyu (2016) Human pluripotent stem cell models of Fragile X syndrome. Mol Cell Neurosci 73:43-51
Weick, Jason P; Held, Dustie L; Bonadurer 3rd, George F et al. (2013) Deficits in human trisomy 21 iPSCs and neurons. Proc Natl Acad Sci U S A 110:9962-7