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

Arqué G, Fotaki V, Fernández D, Martínez de Lagrán M, Arbonés ML, Dierssen M - PLoS ONE (2008)

Bottom Line: Pathogenic aneuploidies involve the concept of dosage-sensitive genes leading to over- and underexpression 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.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.

View Article: PubMed Central - PubMed

Affiliation: Genes and Disease Program, Genomic Regulation Center-CRG, Pompeu Fabra University, Barcelona, Spain.

ABSTRACT

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 degrees C and 17 degrees 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.

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Morris water maze test.Morris water maze performance in Dyrk1A+/− and wild type animals during the learning sessions expressed as (A) latency (s) to find the platform along the acquisition phase, cue and reversal sessions; (B) mean swimming speed; (C) total distance traveled and (D) time spent in the target quadrant during the removal session; discontinuous lines represent the chance level in this session. White bars and circles represent wild types and black bars and circles represent Dyrk1A +/−. Data are represented as mean±SEM; * P<0,05, Student's t test. Abbreviations: REV, reversal session; NE, northeast; NW, northwest; SW, southwest; SE, southeast.
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pone-0002575-g001: Morris water maze test.Morris water maze performance in Dyrk1A+/− and wild type animals during the learning sessions expressed as (A) latency (s) to find the platform along the acquisition phase, cue and reversal sessions; (B) mean swimming speed; (C) total distance traveled and (D) time spent in the target quadrant during the removal session; discontinuous lines represent the chance level in this session. White bars and circles represent wild types and black bars and circles represent Dyrk1A +/−. Data are represented as mean±SEM; * P<0,05, Student's t test. Abbreviations: REV, reversal session; NE, northeast; NW, northwest; SW, southwest; SE, southeast.

Mentions: In the MWM, both Dyrk1A+/− and wild type mice showed a significant reduction of the escape latency along the four sessions of the acquisition phase (MANOVA, “session”: F(3–32) = 24.2, P<0.0001). However, whereas the ability of wild types to reach the hidden platform improved along the acquisition trials (Fig. 1A), Dyrk1A+/− mice did show an improvement in finding the hidden platform only during the first sessions, but their escape latency differed significantly from the wild types in the last sessions (third session P = 0.058, fourth session P = 0.02), and they thus did not reach the same execution levels. As a consequence, the slope of the escape latency curves for Dyrk1A+/− and wild type mice significantly differed (MANOVA F(3, 29) = 24.22, P<0.05). However, the distance traveled was decreased along acquisition sessions in Dyrk1A+/− mice similar to wild types (Fig. 1C). Swim speed and the use non-spatial search strategies are very important in determining the total swim time. In fact, the average swimming speed of Dyrk1A+/− mice was significantly lower with respect to wild types (MANOVA F(3, 33) = 24.22, P<0.01), thus suggesting that the increased escape latency was due at least in part, to a reduced swimming speed (Fig. 1B). However, it should be noted that swimming speed did not change along acquisition sessions in either group of mice (MANOVA, “session”: F(3–32) = 1.04, P = 0.39) and though significant in some sessions, the differences were not very marked (wild type: 12,15 cm.s−1 vs. Dyrk1A+/−: 13.14 cm.s−1, MANOVA, “session”: F(1–16) = 2,182, P = 0.159). Thus we analyzed both non-searching and non-spatial strategies in our mice (see below).


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

Arqué G, Fotaki V, Fernández D, Martínez de Lagrán M, Arbonés ML, Dierssen M - PLoS ONE (2008)

Morris water maze test.Morris water maze performance in Dyrk1A+/− and wild type animals during the learning sessions expressed as (A) latency (s) to find the platform along the acquisition phase, cue and reversal sessions; (B) mean swimming speed; (C) total distance traveled and (D) time spent in the target quadrant during the removal session; discontinuous lines represent the chance level in this session. White bars and circles represent wild types and black bars and circles represent Dyrk1A +/−. Data are represented as mean±SEM; * P<0,05, Student's t test. Abbreviations: REV, reversal session; NE, northeast; NW, northwest; SW, southwest; SE, southeast.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2481280&req=5

pone-0002575-g001: Morris water maze test.Morris water maze performance in Dyrk1A+/− and wild type animals during the learning sessions expressed as (A) latency (s) to find the platform along the acquisition phase, cue and reversal sessions; (B) mean swimming speed; (C) total distance traveled and (D) time spent in the target quadrant during the removal session; discontinuous lines represent the chance level in this session. White bars and circles represent wild types and black bars and circles represent Dyrk1A +/−. Data are represented as mean±SEM; * P<0,05, Student's t test. Abbreviations: REV, reversal session; NE, northeast; NW, northwest; SW, southwest; SE, southeast.
Mentions: In the MWM, both Dyrk1A+/− and wild type mice showed a significant reduction of the escape latency along the four sessions of the acquisition phase (MANOVA, “session”: F(3–32) = 24.2, P<0.0001). However, whereas the ability of wild types to reach the hidden platform improved along the acquisition trials (Fig. 1A), Dyrk1A+/− mice did show an improvement in finding the hidden platform only during the first sessions, but their escape latency differed significantly from the wild types in the last sessions (third session P = 0.058, fourth session P = 0.02), and they thus did not reach the same execution levels. As a consequence, the slope of the escape latency curves for Dyrk1A+/− and wild type mice significantly differed (MANOVA F(3, 29) = 24.22, P<0.05). However, the distance traveled was decreased along acquisition sessions in Dyrk1A+/− mice similar to wild types (Fig. 1C). Swim speed and the use non-spatial search strategies are very important in determining the total swim time. In fact, the average swimming speed of Dyrk1A+/− mice was significantly lower with respect to wild types (MANOVA F(3, 33) = 24.22, P<0.01), thus suggesting that the increased escape latency was due at least in part, to a reduced swimming speed (Fig. 1B). However, it should be noted that swimming speed did not change along acquisition sessions in either group of mice (MANOVA, “session”: F(3–32) = 1.04, P = 0.39) and though significant in some sessions, the differences were not very marked (wild type: 12,15 cm.s−1 vs. Dyrk1A+/−: 13.14 cm.s−1, MANOVA, “session”: F(1–16) = 2,182, P = 0.159). Thus we analyzed both non-searching and non-spatial strategies in our mice (see below).

Bottom Line: Pathogenic aneuploidies involve the concept of dosage-sensitive genes leading to over- and underexpression 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.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.

View Article: PubMed Central - PubMed

Affiliation: Genes and Disease Program, Genomic Regulation Center-CRG, Pompeu Fabra University, Barcelona, Spain.

ABSTRACT

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 degrees C and 17 degrees 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.

Show MeSH
Related in: MedlinePlus