Molecular responses of the Ts65Dn and Ts1Cje mouse models of Down syndrome to MK-801.

Down syndrome (DS), caused by trisomy of human chromosome 21 (chr21), is the most common genetic cause of intellectual disability. The Ts65Dn mouse model of DS is trisomic for orthologs of 94 chr21-encoded, confirmed protein-coding genes and displays a number of behavioral deficits. Recently, Ts65Dn mice were shown to be hypersensitive to the locomotor stimulatory effects of the high-affinity N-methyl-d-aspartate (NMDA) receptor (NMDAR) channel blocker, MK-801. This is consistent with the functions of several chr21 proteins that are predicted directly or indirectly to impact NMDAR function or NMDAR-mediated signaling. In this study, we show that a second mouse model of DS, the Ts1Cje, which is trisomic for 70 protein-coding genes, is also hypersensitive to MK-801. To investigate the molecular basis for the responses to MK-801, we have measured levels of a subset of chr21 and phosphorylated non-chr21 proteins, in the cortex and hippocampus of Ts65Dn and Ts1Cje mice and euploid controls, with and without treatment with MK-801. We show that in euploid mice, the chr21-encoded proteins, TIAM1 and DYRK1A, and phosphorylation of AKT, ERK1/2 and the transcription factor ELK are involved in the MK-801 response. However, in both Ts65Dn and Ts1Cje mice, levels of phosphorylation are constitutively elevated in naïve, unstimulated mice, and the MK-801-induced changes in TIAM1 and DYRK1A and in phosphorylation are either absent or abnormal, with both genotype and brain-region-specific patterns. These results emphasize the complexities of the pathway perturbations that arise with segmental trisomy.

Temporal characteristics of saccadic eye movements induced by auditory stimuli.

Records of horizontal saccadic eye movements made in response to auditory stimuli in the absence of any target related visual stimuli were obtained from two normal human subjects. A band-limiting derivative filter was convolved with records of eye position to obtain estimates of eye velocity. Eye position and velocity records were analyzed off-line to determine the characteristics of the audio-ocular response (AOR). The latency of the AOR decreased with increasing target movement amplitude. The AOR also exhibited lower peak velocity and longer duration than previously reported visually induced saccades. The time at peak velocity increased as saccade amplitude increased until for eye movements with amplitudes greater than 15 degrees, time at peak velocity showed little further increase. Finally, the AOR displayed a high incidence of dynamic overshoot for abducting movements of the right eye and a low incidence of dynamic overshoot for adducting movements of the right eye. System parameters estimated using system identification techniques indicate that the pulse portion of the active state tension driving the agonist muscle is of lower magnitude for auditory saccades than for visual saccades.