dizocilpine-maleate and Down-Syndrome

Down syndrome (DS), caused by trisomy of human chromosome 21 (HSA21), is a common genetic cause of cognitive impairment. This disorder results from the overexpression of HSA21 genes and the resulting perturbations in many molecular pathways and cellular processes. Knowledge-based identification of targets for pharmacotherapies will require defining the most critical protein abnormalities among these many perturbations. Here the authors show that using the Ts65Dn and Ts1Cje mouse models of DS, which are trisomic for 88 and 69 reference protein coding genes, respectively, a simple linear Naïve Bayes classifier successfully predicts behavioral outcome (level of locomotor activity) in response to treatment with the N-methyl-d-aspartate (NMDA) receptor antagonist MK-801. Input to the Naïve Bayes method were simple protein profiles generated from cortex and output was locomotor activity binned into three levels: low, medium, and high. When Feature Selection was used with the Naïve Bayes method, levels of three HSA21 and two non-HSA21 protein features were identified as making the most significant contributions to activity level. Using these five features, accuracies of up to 88% in prediction of locomotor activity were achieved. These predictions depend not only on genotype-specific differences but also on within-genotype individual variation in levels of molecular and behavioral parameters. With judicious choice of pathways and components, a similar approach may be useful in analysis of more complex behaviors, including those associated with learning and memory, and may facilitate identification of novel targets for pharmacotherapeutics.

Topics: Adaptor Proteins, Vesicular Transport; Animals; Artificial Intelligence; Bayes Theorem; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Down Syndrome; Dyrk Kinases; Guanine Nucleotide Exchange Factors; Humans; Locomotion; Mice; Mice, Inbred C57BL; Mice, Transgenic; Nerve Tissue Proteins; Neuroprotective Agents; Predictive Value of Tests; Protein Serine-Threonine Kinases; Protein-Tyrosine Kinases; Statistics as Topic

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.

Topics: Animals; Behavior, Animal; Blotting, Western; Data Interpretation, Statistical; Dizocilpine Maleate; Dose-Response Relationship, Drug; Down Syndrome; Excitatory Amino Acid Antagonists; Individuality; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Phosphorylation

Individuals with Down syndrome (DS) and Ts65Dn mice (a major animal model of DS) carry an extra copy of the DSCR1 (Down Syndrome Critical Region 1) gene, which encodes for a protein that inhibits calcineurin. Calcineurin itself has been shown to modulate N-methyl-D-aspartate (NMDA) receptor (NMDAR) activation kinetics by decreasing channel mean open time and opening probability. We hypothesize that the overexpression of DSCR1 in persons with DS and Ts65Dn mice would inhibit normal calcineurin activity and produce pathological increases in NMDAR mean open time and opening probability. These kinetic changes should in turn produce an increase in inhibition of NMDAR-mediated currents by open channel blockers. To test this hypothesis, we investigated the locomotor-stimulating effects of MK-801 on Ts65Dn mice and have found that these mice display an increased sensitivity to this compound. Furthermore, we have found that acute injections (5 mg/kg, i.p.) of the uncompetitive NMDAR antagonist memantine rescue performance deficits of Ts65Dn mice on a fear conditioning test. Because the actions of memantine on NMDAR kinetics had been shown by others to mimic somewhat the actions of calcineurin, we attributed this positive effect of memantine on Ts65Dn mice to a drug-mediated 'normalization' of NMDAR function. To our knowledge, this is the first instance in which the acute injection of a pharmacological agent has improved the behavioral performance of Ts65Dn mice in a test of learning and memory. These results are very promising from a potential therapeutic perspective, given memantine's current status as a Food and Drug Administration (FDA)-approved drug.

Topics: Age Factors; Analysis of Variance; Animals; Behavior, Animal; Conditioning, Psychological; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Down Syndrome; Excitatory Amino Acid Antagonists; Fear; Learning; Male; Memantine; Mice; Mice, Inbred C57BL; Mice, Neurologic Mutants; Mice, Transgenic; Motor Activity