Impaired spatial learning strategies and novel object recognition in mice haploinsufficient for the dual specificity tyrosine-regulated kinase-1A (Dyrk1A)

BACKGROUND: Pathogenic aneuploidies involve the concept of dosage-sensitive genes leading to over- and underexpression phenotypes. Monosomy 21 in human leads to mental retardation and skeletal, immune and respiratory function disturbances. Most of the human condition corresponds to partial monosomies suggesting that critical haploinsufficient genes may be responsible for the phenotypes. The DYRK1A gene is localized on the human chromosome 21q22.2 region, and has been proposed to participate in monosomy 21 phenotypes. It encodes a dual-specificity kinase involved in neuronal development and in adult brain physiology, but its possible role as critical haploinsufficient gene in cognitive function has not been explored. METHODOLOGY/PRINCIPAL FINDINGS: We used mice heterozygous for a Dyrk1A targeted mutation (Dyrk1A+/−) to investigate the implication of this gene in the cognitive phenotypes of monosomy 21. Performance of Dyrk1A+/− mice was assayed 1/ in a navigational task using the standard hippocampally related version of the Morris water maze, 2/ in a swimming test designed to reveal potential kinesthetic and stress-related behavioral differences between control and heterozygous mice under two levels of aversiveness (25°C and 17°C) and 3/ in a long-term novel object recognition task, sensitive to hippocampal damage. Dyrk1A+/− mice showed impairment in the development of spatial learning strategies in a hippocampally-dependent memory task, they were impaired in their novel object recognition ability and were more sensitive to aversive conditions in the swimming test than euploid control animals. CONCLUSIONS/SIGNIFICANCE: The present results are clear examples where removal of a single gene has a profound effect on phenotype and indicate that haploinsufficiency of DYRK1A might contribute to an impairment of cognitive functions and stress coping behavior in human monosomy 21

Regulator of calcineurin 1 mediates pathological vascular wall remodeling

Angiotensin-II–driven calcineurin activation and regulator of calcineurin-1 (Rcan-1) expression is required for pathological vascular remodeling in mice

Overexpression of Dyrk1A Is Implicated in Several Cognitive, Electrophysiological and Neuromorphological Alterations Found in a Mouse Model of Down Syndrome

Down syndrome (DS) phenotypes result from the overexpression of several dosage-sensitive genes. The DYRK1A (dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A) gene, which has been implicated in the behavioral and neuronal alterations that are characteristic of DS, plays a role in neuronal progenitor proliferation, neuronal differentiation and long-term potentiation (LTP) mechanisms that contribute to the cognitive deficits found in DS. The purpose of this study was to evaluate the effect of Dyrk1A overexpression on the behavioral and cognitive alterations in the Ts65Dn (TS) mouse model, which is the most commonly utilized mouse model of DS, as well as on several neuromorphological and electrophysiological properties proposed to underlie these deficits. In this study, we analyzed the phenotypic differences in the progeny obtained from crosses of TS females and heterozygous Dyrk1A (+/-) male mice. Our results revealed that normalization of the Dyrk1A copy number in TS mice improved working and reference memory based on the Morris water maze and contextual conditioning based on the fear conditioning test and rescued hippocampal LTP. Concomitant with these functional improvements, normalization of the Dyrk1A expression level in TS mice restored the proliferation and differentiation of hippocampal cells in the adult dentate gyrus (DG) and the density of GABAergic and glutamatergic synapse markers in the molecular layer of the hippocampus. However, normalization of the Dyrk1A gene dosage did not affect other structural (e.g., the density of mature hippocampal granule cells, the DG volume and the subgranular zone area) or behavioral (i.e., hyperactivity/attention) alterations found in the TS mouse. These results suggest that Dyrk1A overexpression is involved in some of the cognitive, electrophysiological and neuromorphological alterations, but not in the structural alterations found in DS, and suggest that pharmacological strategies targeting this gene may improve the treatment of DS-associated learning disabilities

Data from: Overexpression of Dyrk1A is implicated in several cognitive, electrophysiological and neuromorphological alterations found in a mouse model of Down syndrome

Down syndrome (DS) phenotypes result from the overexpression of several dosage-sensitive genes. The DYRK1A (dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A) gene, which has been implicated in the behavioral and neuronal alterations that are characteristic of DS, plays a role in neuronal progenitor proliferation, neuronal differentiation and long-term potentiation (LTP) mechanisms that contribute to the cognitive deficits found in DS. The purpose of this study was to evaluate the effect of Dyrk1A overexpression on the behavioral and cognitive alterations in the Ts65Dn (TS) mouse model, which is the most commonly utilized mouse model of DS, as well as on several neuromorphological and electrophysiological properties proposed to underlie these deficits. In this study, we analyzed the phenotypic differences in the progeny obtained from crosses of TS females and heterozygous Dyrk1A (+/−) male mice. Our results revealed that normalization of the Dyrk1A copy number in TS mice improved working and reference memory based on the Morris water maze and contextual conditioning based on the fear conditioning test and rescued hippocampal LTP. Concomitant with these functional improvements, normalization of the Dyrk1A expression level in TS mice restored the proliferation and differentiation of hippocampal cells in the adult dentate gyrus (DG) and the density of GABAergic and glutamatergic synapse markers in the molecular layer of the hippocampus. However, normalization of the Dyrk1A gene dosage did not affect other structural (e.g., the density of mature hippocampal granule cells, the DG volume and the subgranular zone area) or behavioral (i.e., hyperactivity/attention) alterations found in the TS mouse. These results suggest that Dyrk1A overexpression is involved in some of the cognitive, electrophysiological and neuromorphological alterations, but not in the structural alterations found in DS, and suggest that pharmacological strategies targeting this gene may improve the treatment of DS-associated learning disabilities

Regulated Segregation of Kinase Dyrk1A during Asymmetric Neural Stem Cell Division Is Critical for EGFR-Mediated Biased Signaling

SummaryStem cell division can result in two sibling cells exhibiting differential mitogenic and self-renewing potential. Here, we present evidence that the dual-specificity kinase Dyrk1A is part of a molecular pathway involved in the regulation of biased epidermal growth factor receptor (EGFR) signaling in the progeny of dividing neural stem cells (NSC) of the adult subependymal zone (SEZ). We show that EGFR asymmetry requires regulated sorting and that a normal Dyrk1a dosage is required to sustain EGFR in the two daughters of a symmetrically dividing progenitor. Dyrk1A is symmetrically or asymmetrically distributed during mitosis, and biochemical analyses indicate that it prevents endocytosis-mediated degradation of EGFR by a mechanism that requires phosphorylation of the EGFR signaling modulator Sprouty2. Finally, Dyrk1a heterozygous NSCs exhibit defects in self-renewal, EGF-dependent cell-fate decisions, and long-term persistence in vivo, suggesting that symmetrical divisions play a role in the maintenance of the SEZ reservoir

Data PONE-D-14-18420

This is an excel file containing the data underlying the results described in each manuscript. This file contains 11 spreadsheets, containing the raw data of 1) Dyrk1A protein levels, 2) MWM performance, 3) CFC performance, 4) Rotarod Performance, 5) Open Field performance, 6) LTP results, 7) GAD65/67 and VGLUT levels and VGLUT/GAD65/67 ratio, 8) Ki67, DCX, CLR and DAPI values, 9) DG volume and SGZ ratio, 10) Body weight and 11) Motor tests dat

Normalization of the <i>Dyrk1A</i> copy number did not affect motor coordination in the rotarod test or the levels of general activity and anxiety in the open field test.

<p>Mean values ± SEM of the latency to fall from the rotarod at different constant speeds (<b>a</b>) and during the acceleration cycle (<b>b</b>) or of the activity performed by the three groups of mice in the open field test (<b>c</b>). Rotarod constant speeds: ANOVA ‘trisomy’: F(1,35) = 0.72, p = 0.40; ‘Dyrk1A’: F(1,35) = 1.82, p = 0.18. Acceleration cycle: ANOVA ‘trisomy’: F(1,35) = 0.72, p = 0.40; ‘Dyrk1A’: F(1,35) = 1.69, p = 0.20. Open field periphery: ANOVA ‘trisomy’: F(1,35) = 6.36, p = 0.014; ‘Dyrk1A’: F(1,35) = 0.70, p = 0.17; Center: ANOVA ‘trisomy’: F(1,31) = 2.21, p = 0.14; ‘Dyrk1A’: F(1,31) = 0.17, p = 0.68; Total: ANOVA ‘trisomy’: F(1,35) = 5.39, p = 0.023; ‘Dyrk1A’: F(1,35) = 1.77, p = 0.67. *: p<0.05 TS +/+/+ vs. CO +/+; Bonferroni tests after significant MANOVAs.</p

Normalization of the <i>Dyrk1A</i> copy number reduced the density of GABAergic and increased the density of glutamatergic synapse markers in the hippocampus of TS mice.

<p>(<b>a</b>) Representative images of GAD65/67, VGLUT and GAD6567/VGLUT immunostaining. (<b>b</b>) Mean values ± SEM of the percentage of area occupied by GAD65/67- (top row) and VGLUT-positive boutons (middle row) in the hippocampus of TS +/+/+, TS +/+/− and CO +/+ mice and the ratio of these areas (lower row). GAD65/67: ANOVA ‘trisomy’: F(1,17) = 10.10, p = 0.006; ‘<i>Dyrk1A</i>’: F(1,17) = 3.91, p = 0.066. VGLUT: ANOVA ‘trisomy’: F(1,17) = 10.35, p = 0.006; ‘<i>Dyrk1A</i>’: F(1,17) = 4.49, p = 0.051; Ratio GAD/VGLUT: ANOVA ‘trisomy’: F(1,17) = 37.44, p<0.001; ‘<i>Dyrk1A</i>’: F(1,23) = 9.30, p = 0.009. **: p<0.01, ***: p<0.001 TS +/+/+ vs. CO +/+; #: p<0.05 TS +/+/+ vs. TS +/+/−.</p