Neuroscience and Membrane Biology
The principal research interests of this laboratory are concerned with understanding how cognitive and neurodegeneration disorders such as Down syndrome (DS) and Alzheimer’s disease may result from abnormal brain development and increased apoptosis. We are specifically concerned with understanding mechanisms of brain development and aging deficits in the trisomy 16 (Ts16) mouse, a such as neuronal proliferation, differentiation, and death. Our most recent work has focused on neurological potential animal model for impaired neuron survival, defective Ca2+ Alzheimer’s disease and Down syndrome. We have found that there is abnormal neuronal proliferation, homeostasis in astrocytes and neurons, and spatial learning and memory deficits.

Abnormal Cortical Development
We have determined that cerebral cortical development in Ts16 occurs abnormally. Tangential expansion of the cortex is slowed in Ts16 resulting in a reduction of final telencephalic size. In addition, there is a delay in the growth of the postmitotic layers of the cortex during mid-gestation, but the radial growth of the cortex attains normal thickness during the later part of the embryonic period. These defects constitute a distinctive phenotype in Ts16 which is similar to what is known about DS cortical development. We have determined that abnormalities in neuroblast proliferation and apoptosis contribute to this phenotype. Cell cycle duration is increased in Ts16 neuroblasts due to a longer DNA synthetic phase, and fewer cells in the Ts16 ventricular germinal zone become postmitotic and leave the germinal zone than in diploid litermates. During this period of excessive neuron generation in Ts16, we have observed a large increase in apoptosis in both the germinal zone and in postmitotic layers, suggesting that the increased death acts to compensate for the overproduction of neurons. In addition, since the timing of this delay in radial growth coincides with initial formation of cortical connections, we are investigating whether the delay leads to abnormal connectivity in the Ts16 that parallels abnormalities occurring in DS; studies are underway to test whether in DS similar developmental cortex. These developmental disorders in the Ts16 mouse cortex predict later cognitive dysfunction. In the partial Ts16 mouse (that survives to adulthood), we have found deficits in spatial learnimg and memory (below). Studies are currently underway to investigate whether similar abnormalities during cortical development occur in DS.