Trisomy 21 results in the constellation of phenotypes collectively termed Down syndrome (DS) and is one of the most prevalent congenital birth defects. Motor and sensory deficits and often severe mental retardation are among the many debilitating sequelae of DS. Although the precise causes of cognitive impairment in DS are not known, these abnormalities are thought to be due to altered brain development as changes in cell number and volume are found in neocortex, hippocampus and cerebellum in the perinatal and juvenile postmortem brain. A comprehensive understanding of the . etiology of the DS cognitive phenotype therefore requires examination of early prenatal development, but this analysis has never been conducted as it is hampered by challenges obtaining staged human embryonic tissue and by breeding difficulties in mouse models of DS. We have addressed this problem by generating a breeding colony of the Ts65Dn mouse model of DS and have used this resource to determine the effect of trisomy on embryonic development of the cerebral cortex and hippocampus. We have uncovered substantial over-production of inhibitory neurons in the Ts65Dn cerebral cortex and hippocampus which may lead to increased inhibitory drive and abnormal morphogenesis of these forebrain regions. These two areas are known to be affected in the DS brain. Using cellular, molecular and electrophysiological techniques, we wi II determine how altered development in Ts65Dn leads to functional changes in the maturing neuronal circuits in the neocortex and hippocampus. These experiments will define the underlying developmental causative factors of cognitive impairment in DS at both the cellular and physiological levels and are therefore important for the future development of prevention or treatment strategies.
Our preliminary data in mouse models of Down syndrome indicate that early brain development is transiently disrupted prior to appearance of deficits in synaptic connections in the cerebral cortex and hippocampus. Our goal in this study is to fully characterize the abnormalities in early brain development and to elucidate the ensuing changes in neuronal function and synapse formation. We have elucidated the possible role of two transcription factor genes in these developmental abnormalities and will perform a genetic rescue experiment in the Ts65Dn animal model of Down syndrome to confirm their roles in DS brain development. These studies will therefore provide a full description of the developmental brain anomaly found during Down syndrome development and will potentially lead to strategies aimed at preventing cognitive dysfunction in Down syndrome.
