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

Abstract

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 highaffinity 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 proteincoding 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.

Exaggerated NMDA mediated LTD in a mouse model of Down syndrome and pharmacological rescuing by memantine

“…Inhibition of CaN activity alters NMDAR gating kinetics (Lieberman and Mody 1994) and causes increased sensitivity to the stimulatory locomotor actions of the NMDAR antagonist MK-801 (Miyakawa et al 2003). The Ts65Dn and Ts1Cje mouse models of DS display similar hypersensitivity to these psychotomimetic actions of MK-801 Siddiqui et al 2008), which supports the hypothesis that CaN is inhibited in these animal models and that, consequently, NMDAR function may indeed be altered. In addition, we also have found that acute doses of the low-affinity uncompetitive NMDAR antagonist memantine rescue learning and memory deficits in Ts65Dn mice in a fearconditioning test ).…”

“…Our research team has found previously that the Ts65Dn mouse displays pharmacological responses consistent with dysfunction in molecular pathways coupled to the gating of NMDARs Siddiqui et al 2008). Proteins encoded by nine genes located on chromosome 21 and in the Ts65Dn trisomic segment (APP, TIAM1, BACH1, SOD1, SYNJ1, ITSN1, RCAN1, DYRK1A, and PCP4) have been shown to interact either directly with NMDARs, or indirectly via the protein phosphatase calcineurin (CaN) (Siddiqui et al 2008;Gardiner 2010).…”

“…Proteins encoded by nine genes located on chromosome 21 and in the Ts65Dn trisomic segment (APP, TIAM1, BACH1, SOD1, SYNJ1, ITSN1, RCAN1, DYRK1A, and PCP4) have been shown to interact either directly with NMDARs, or indirectly via the protein phosphatase calcineurin (CaN) (Siddiqui et al 2008;Gardiner 2010). Inhibition of CaN activity alters NMDAR gating kinetics (Lieberman and Mody 1994) and causes increased sensitivity to the stimulatory locomotor actions of the NMDAR antagonist MK-801 (Miyakawa et al 2003).…”

NMDA-Mediated Regulation ofDSCAMDendritic Local Translation Is Lost in a Mouse Model of Down's Syndrome

“…9). In support of this idea, Ts1Cje are hypersensitive to the channel blocker MK-801 [(ϩ)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate], suggesting dysregulation of NMDAR signaling (Siddiqui et al, 2008). We hypothesize that impairment of NMDA regulation of local dendritic mRNA translation, such as that of DSCAM, may contribute to deficits in dendrite morphology and/or synaptic plasticity in DS.…”

Combinatorial Gene Effects on the Neural Progenitor Pool in Down Syndrome

“…Altered neurite formation, abnormal dendrite spines (Matsuo et al, 2002;Siddiqui et al, 2008;Tolias et al, 2005;Tolias et al, 2007) SOD1 APP Increase ROS, mitochondrial dysfunction…”