Behavioral Characterization of a Mouse Model Overexpressing DSCR1/ RCAN1

Mara Dierssen,Gloria Arqué,Cristina Fillat,Jerome Mcdonald,Nuria Andreu,Jesús Flórez,Carmen Martínez-Cué,Georges Chapouthier

doi:10.1371/journal.pone.0017010

Abstract

DSCR1/ RCAN1 is a chromosome 21 gene found to be overexpressed in the brains of Down syndrome (DS) and postulated as a good candidate to contribute to mental disability. However, even though Rcan1 knockout mice have pronounced spatial learning and memory deficits, the possible deleterious effects of its overexpression in DS are not well understood. We have generated a transgenic mouse model overexpressing DSCR1/RCAN1 in the brain and analyzed the effect of RCAN1 overexpression on cognitive function. TgRCAN1 mice present a marked disruption of the learning process in a visuo-spatial learning task. However, no significant differences were observed in the performance of the memory phase of the test (removal session) nor in a step-down passive avoidance task, thus suggesting that once learning has been established, the animals are able to consolidate the information in the longer term.

Highlights

Mental disability in individuals with Down syndrome (DS) is produced by the increased expression of some of the 231 supernumerary genes on the extra copy of chromosome 21
Efforts to identify genes on human chromosome 21 with the potential to cause the brain anomalies observed in Down syndrome (DS), led to the discovery of a gene, Down syndrome candidate region-1 (DSCR1) renamed RCAN1 (Regulator of Calcineurin-1)
RCAN1 is a modulator of calcineurin, a protein phosphatase known to function in a variety of cellular processes, among which learning and memory are relevant for the mental impairment seen in DS

Summary

Introduction

Mental disability in individuals with Down syndrome (DS) is produced by the increased expression of some of the 231 supernumerary genes on the extra copy of chromosome 21 One such gene is Down’s syndrome candidate region-1 (DSCR1, known as RCAN1) [1,2], which encodes a protein that is a functional inhibitor of calcineurin, a ubiquitous and multifunctional calcium-activated protein phosphatase. Mouse models of RCAN1 overexpression have shown a role of RCAN1 regulating exocytosis in chromaffin cells and in mutant huntingtin phosphorilation, suggesting a role of RCAN1 in the Alzheimer’s disease neuropathology associated to DS and in Huntington’s disease [8,9,10] It has been identified as a gene involved in cognitive symptoms of schizophrenia patients by measuring differences in DNA copy number variants [11]. The in vivo relevance of Rcan overexpression and its possible contribution to DS cognitive phenotypes has not yet been explored

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