Electrical studies of cultured fetal human trisomy 21 and mouse trisomy 16 neurons identify functional deficits that may lead to mental retardation in Down syndrome

There are no consistent and disease-specific anatomic changes in brains of fetuses and young healthy adults with Down syndrome (trisomy 21; Ts21). Thus, it is likely that mental retardation in Down syndrome is due to functional abnormalities in brain neurons and their networks. This interpretation is consistent with electrophysiological studies of cultured neurons from human Ts21 and mouse trisomy 16 (Ts16) fetuses. Fetal Ts21 dorsal root ganglia (DRG) neurons demonstrate a shortened action potential with accelerated depolarization and repolarization due to accelerated kinetics of inward Na and outward K currents as compared with normal diploid human DRG neurons. Cultured DRG neurons from the Ts16 but not from the trisomy 19 fetal mouse show similar abnormalities. Thus, the Ts16 mouse is an appropriate model of neuronal dysfunction in Down syndrome. In contrast, mouse Ts16 hippocampal neurons exhibit slowed depolarization of the action potential and a reduced inward Na current due to fewer Na channels, as well as an increased voltage-dependent inward Ca current mediated by an L-type Ca channel. Abnormal active membrane properties exist also in mouse Ts16 septal neurons, different from those in Ts16 DRG and hippocampal neurons. These results suggest that Ts21/Ts16 leads to dysregulation of neuron-specific active ionic currents, possibly by influencing subunits that compose ion channels which determine these currents. During brain development and maturation, abnormal neuronal electrical properties can lead to abnormal development of synapses and neural networks. Suboptimal integrated brain activity resulting from these changes is postulated to contribute to mental retardation in Down syndrome.