Impaired Spatial Learning Strategies and Novel Object Recognition in Mice Haploinsufficient for the Dual Specificity Tyrosine-Regulated Kinase-1A (Dyrk1A)

Abstract

BackgroundPathogenic 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 FindingsWe 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/SignificanceThe 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.

Ten new cases further delineate the syndromic intellectual disability phenotype caused by mutations in DYRK1A

“…DYRK1A has been shown to positively regulate brain size by controlling neuronal precursor proliferation, neuronal differentiation and synaptogenesis and survival, particularly in the optic lobes, superior colliculus, central brain hemispheres and hippocampus. 18,19,21,44,45 The reduced brain size may be partially explained by the dual role of DYRK1A in inhibiting the proliferation of neuronal progenitors via suppression of NOTCH signaling and Cyclin D1 while also promoting neurogenesis by stabilizing the cyclindependent kinase inhibitor p27 (KIP1) . 46,47 In addition, DYRK1A interacts with the microtubule and actin cytoskeletal networks to regulate neurite outgrowth and synaptogenesis.…”

“…18 DYRK1A haploinsufficiency in mice results in a smaller brain size, developmental delay, 19 decreased motor function, 20 cognitive impairment and adverse stress coping behavior. 21 Patients with partial monosomy 21 or rearrangements that involve DYRK1A and other contiguous genes have been described with phenotypes similar to the ones found in DYRK1A ortholog-deficient animal models including microcephaly, ID and developmental delay. [22][23][24][25][26] Seven previously reported patients with chromosomal rearrangements, microdeletions or truncating mutations that disrupted specifically DYRK1A had ID, microcephaly, speech delay/ absence and feeding dysfunction.…”

Ceramide Levels Regulated by Carnitine Palmitoyltransferase 1C Control Dendritic Spine Maturation and Cognition

“…Morris Water Maze (MWM) Test-To test hippocampus-dependent spatial cognition, the MWM test was used, as described elsewhere (12). The water maze consisted of a circular pool (diameter 1.20 m, height 0.5 m).…”

Development of a novel selective inhibitor of the Down syndrome-related kinase Dyrk1A

“…Interestingly, mice that have only one copy of Dyrk1A through targeted disruption of Dyrk1A in one allele (Dyrk1A + / − mice) also show profound phenotypic abnormalities, including reduced viability, smaller body size, disproportionate decrease in the size of the midbrain and hindbrain regions, changes in pyramidal cell structure and neuromotor and cognitive impairment [23][24][25][26] . The mice homozygous for targeted disruption of Dyrk1A (Dyrk1A − / − -null mice) are embryonic lethal and died between E10.5 and E13.5 23 .…”