The goal of this research program is to investigate the development of the cerebral cortex of the segmental trisomy 16 (Ts65Dn) mouse, a potential animal model of Down syndrome (DS, trisomy 21). Many of the same chromosome 21 genes triplicated in DS are also triplicated in Ts65Dn and therefore, DS and Ts65Dn share a common genetic abnormality. Both DS and Ts65Dn have deficits in spatial learning and memory that are consistent with functional impairment in the frontal cortex. However, there is little information available about the development of the frontal cortex in Ts65Dn. The investigators hypothesize that the spatial learning and memory deficits in Ts65Dn are due to abnormalities in the generation, maturation, and survival of neurons during prenatal neuronogenesis and/or early postnatal neocortical development. The proposed experiments probe the behavior of neuroblasts and young postmitotic neurons in the developing neocortex. During the neuronogenic period, neurons are born and migrate to their final locations and the formation of connections begins. Abnormalities occurring during this period could lead to delayed formation of the pallial layers and cortical connections. During early postnatal life, synapses are formed, interneuronal connections are firmly established, and extra neurons are removed by programmed cell death. Abnormalities during this period could lead to abnormal dendritic organization and synaptogenesis, loss of connections and inappropriate programmed cell death. Defects in neuroblast proliferation, synaptogenesis, connectivity, and programmed cell death during neocortical development could lead to permanent cortical abnormalities responsible for the cognitive deficits in Ts65Dn. Similar defects in human brain development could lead to cognitive deficits in DS.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Small Research Grants (R03)
Project #
1R03HD037197-01A1
Application #
2902285
Study Section
Special Emphasis Panel (ZRG1-BDCN-5 (01))
Program Officer
Hanson, James W
Project Start
1999-07-01
Project End
2001-06-30
Budget Start
1999-07-01
Budget End
2000-06-30
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Maryland Baltimore
Department
Pharmacology
Type
Schools of Medicine
DUNS #
003255213
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Cheng, Aiwu; Haydar, Tarik F; Yarowsky, Paul J et al. (2004) Concurrent generation of subplate and cortical plate neurons in developing trisomy 16 mouse cortex. Dev Neurosci 26:255-65
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