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Behavioral characterization of a mouse model overexpressing DSCR1/ RCAN1.

Dierssen M, Arqué G, McDonald J, Andreu N, Martínez-Cué C, Flórez J, Fillat C - PLoS ONE (2011)

Bottom Line: 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.We have generated a transgenic mouse model overexpressing DSCR1/RCAN1 in the brain and analyzed the effect of RCAN1 overexpression on cognitive function.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.

View Article: PubMed Central - PubMed

Affiliation: Centre for Genomic Regulation, Barcelona Biomedical Research Park, and CIBER de Enfermedades Raras, Barcelona, Catalonia, Spain. mara.dierssen@crg.es

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.

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Visuo-spatial learning in the Morris water maze.Morris water maze performance of TgRCAN1 and wild type animals during the learning sessions expressed as (left panel) latency (s) to reach the platform along the acquisition phase, cue and reversal sessions. A clear deficit was observed in TgRCAN1 in all learning phases; (Right panel) Cumulative search-error on training trials and a learning index (Gallagher's proximity index) computed from the trials over the course of training. This measure relies on a computation of distance from the platform during the trial [17] and clearly indicated the use of poorer learning strategies in transgenic mice. White squares represent wild types and black squares represent TgRCAN1. Data are represented as mean ± S.E.M. *P<0.05, **P<0.01.
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pone-0017010-g003: Visuo-spatial learning in the Morris water maze.Morris water maze performance of TgRCAN1 and wild type animals during the learning sessions expressed as (left panel) latency (s) to reach the platform along the acquisition phase, cue and reversal sessions. A clear deficit was observed in TgRCAN1 in all learning phases; (Right panel) Cumulative search-error on training trials and a learning index (Gallagher's proximity index) computed from the trials over the course of training. This measure relies on a computation of distance from the platform during the trial [17] and clearly indicated the use of poorer learning strategies in transgenic mice. White squares represent wild types and black squares represent TgRCAN1. Data are represented as mean ± S.E.M. *P<0.05, **P<0.01.

Mentions: We used the standard paradigm of the Morris water maze to analyze the visuo-spatial learning and memory profile in TgRCAN1 mice (Fig. 3). No genotype-related differences were observed in the training session, as demonstrated by the similar escape latency (ANOVA, F(1,25) = 2.96; P = 0.87) and distance travelled (data not shown), although a tendency to perform worse the procedural learning task was detected in transgenic mice. Along the acquisition sessions, all groups of animals were efficient in learning the location of the platform as indicated by the progressive decrease in escape latency (repeated measures ANOVA, wild type, F(1,23) = 100.7, P = 0.0001; TgRCAN1, F(1,16) = 110.5, P = 0.0001) and distance travelled (repeated measures ANOVA, P<0.001). However, an important learning impairment was detected in TgRCAN1 (repeated measures ANOVA, “session×genotype”, F(1,28) = 14.11, P<0.001) mice as shown by the increased latencies (Fig. 3, left panel) to reach the platform and distances (repeated measures ANOVA, “session×genotype”, F(1,28) = 16.14, P<0.001) Fig. 3, right panel) travelled across acquisition sessions. This was specifically related to learning problems since swimming speed was not affected and in the cued session, where the goal was to find a visible platform (black stripped flag), no differences were detected in the latency to reach the platform when it was made visible (ANOVA, F(1,40) = 1.08; P = 0.31) suggesting that RCAN1 overexpression did not produce significant motor or motivational problems. During the probe trial that is a measure of the visuo-spatial memory, the latency to cross the annulus of the hidden escape platform and the number of crosses was similar between genotypes thus suggesting that once learned the information is retained in transgenic mice. Moreover, in both groups we observed a significantly higher preference for the trained quadrant (northwest), as shown by the percentage of time spent in the trained quadrant (ANOVA, wild-type, F(1,23) = 58.6, P = 0.001 and TgRCAN1, F(1,16) = 56.7, P = 0.001). These observations support the conclusion that TgRCAN1 mice indeed remember the location of the platform. Finally, in the reversal session the efficiency to unlearn the old platform position and learn a new one was not altered in TgRCAN1.


Behavioral characterization of a mouse model overexpressing DSCR1/ RCAN1.

Dierssen M, Arqué G, McDonald J, Andreu N, Martínez-Cué C, Flórez J, Fillat C - PLoS ONE (2011)

Visuo-spatial learning in the Morris water maze.Morris water maze performance of TgRCAN1 and wild type animals during the learning sessions expressed as (left panel) latency (s) to reach the platform along the acquisition phase, cue and reversal sessions. A clear deficit was observed in TgRCAN1 in all learning phases; (Right panel) Cumulative search-error on training trials and a learning index (Gallagher's proximity index) computed from the trials over the course of training. This measure relies on a computation of distance from the platform during the trial [17] and clearly indicated the use of poorer learning strategies in transgenic mice. White squares represent wild types and black squares represent TgRCAN1. Data are represented as mean ± S.E.M. *P<0.05, **P<0.01.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3045383&req=5

pone-0017010-g003: Visuo-spatial learning in the Morris water maze.Morris water maze performance of TgRCAN1 and wild type animals during the learning sessions expressed as (left panel) latency (s) to reach the platform along the acquisition phase, cue and reversal sessions. A clear deficit was observed in TgRCAN1 in all learning phases; (Right panel) Cumulative search-error on training trials and a learning index (Gallagher's proximity index) computed from the trials over the course of training. This measure relies on a computation of distance from the platform during the trial [17] and clearly indicated the use of poorer learning strategies in transgenic mice. White squares represent wild types and black squares represent TgRCAN1. Data are represented as mean ± S.E.M. *P<0.05, **P<0.01.
Mentions: We used the standard paradigm of the Morris water maze to analyze the visuo-spatial learning and memory profile in TgRCAN1 mice (Fig. 3). No genotype-related differences were observed in the training session, as demonstrated by the similar escape latency (ANOVA, F(1,25) = 2.96; P = 0.87) and distance travelled (data not shown), although a tendency to perform worse the procedural learning task was detected in transgenic mice. Along the acquisition sessions, all groups of animals were efficient in learning the location of the platform as indicated by the progressive decrease in escape latency (repeated measures ANOVA, wild type, F(1,23) = 100.7, P = 0.0001; TgRCAN1, F(1,16) = 110.5, P = 0.0001) and distance travelled (repeated measures ANOVA, P<0.001). However, an important learning impairment was detected in TgRCAN1 (repeated measures ANOVA, “session×genotype”, F(1,28) = 14.11, P<0.001) mice as shown by the increased latencies (Fig. 3, left panel) to reach the platform and distances (repeated measures ANOVA, “session×genotype”, F(1,28) = 16.14, P<0.001) Fig. 3, right panel) travelled across acquisition sessions. This was specifically related to learning problems since swimming speed was not affected and in the cued session, where the goal was to find a visible platform (black stripped flag), no differences were detected in the latency to reach the platform when it was made visible (ANOVA, F(1,40) = 1.08; P = 0.31) suggesting that RCAN1 overexpression did not produce significant motor or motivational problems. During the probe trial that is a measure of the visuo-spatial memory, the latency to cross the annulus of the hidden escape platform and the number of crosses was similar between genotypes thus suggesting that once learned the information is retained in transgenic mice. Moreover, in both groups we observed a significantly higher preference for the trained quadrant (northwest), as shown by the percentage of time spent in the trained quadrant (ANOVA, wild-type, F(1,23) = 58.6, P = 0.001 and TgRCAN1, F(1,16) = 56.7, P = 0.001). These observations support the conclusion that TgRCAN1 mice indeed remember the location of the platform. Finally, in the reversal session the efficiency to unlearn the old platform position and learn a new one was not altered in TgRCAN1.

Bottom Line: 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.We have generated a transgenic mouse model overexpressing DSCR1/RCAN1 in the brain and analyzed the effect of RCAN1 overexpression on cognitive function.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.

View Article: PubMed Central - PubMed

Affiliation: Centre for Genomic Regulation, Barcelona Biomedical Research Park, and CIBER de Enfermedades Raras, Barcelona, Catalonia, Spain. mara.dierssen@crg.es

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.

Show MeSH
Related in: MedlinePlus