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Unconventional transcriptional response to environmental enrichment in a mouse model of Rett syndrome.

Kerr B, Silva PA, Walz K, Young JI - PLoS ONE (2010)

Bottom Line: RTT is characterized by psychomotor retardation, purposeless hand movements, autistic-like behavior and abnormal gait.We found that EE delayed and attenuated some neurological alterations presented by Mecp2(-/y) mice and prevented the development of motor discoordination and anxiety-related abnormalities.We found that EE induced downregulation of several synaptic markers, suggesting that the partial prevention of RTT-associated phenotypes is achieved through a non-conventional transcriptional program.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, Centro de Estudios Científicos, Valdivia, Chile.

ABSTRACT

Background: Rett syndrome (RTT) is an X-linked postnatal neurodevelopmental disorder caused by mutations in the gene encoding methyl-CpG binding protein 2 (MeCP2) and one of the leading causes of mental retardation in females. RTT is characterized by psychomotor retardation, purposeless hand movements, autistic-like behavior and abnormal gait. We studied the effects of environmental enrichment (EE) on the phenotypic manifestations of a RTT mouse model that lacks MeCP2 (Mecp2(-/y)).

Principal findings: We found that EE delayed and attenuated some neurological alterations presented by Mecp2(-/y) mice and prevented the development of motor discoordination and anxiety-related abnormalities. To define the molecular correlate of this beneficial effect of EE, we analyzed the expression of several synaptic marker genes whose expression is increased by EE in several mouse models.

Conclusions/significance: We found that EE induced downregulation of several synaptic markers, suggesting that the partial prevention of RTT-associated phenotypes is achieved through a non-conventional transcriptional program.

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Related in: MedlinePlus

Environmental Enrichment improves neuromotor dysfunction in Mecp2−/y mice.A, Footprint analysis showed impaired walking patterns in Mecp2−/y-SC mice compared with Mecp2−/y-EE and Mecp2+/y−SC control animals. B, Measures taken for footprint analysis .C, Speed of movement (cm/s) was faster for Mecp2−/y-EE than Mecp2−/y-SC mice. D, Mecp2−/y-EE mice displayed improved motor coordination compared with Mecp2−/y-SC evidenced by a shorter time to reach the platform for the first time and E, higher number of arrivals to the platform in the elevated beam test. The total number of animals in each group is shown (n). Mean ± SEM values are presented. A two-way repeated measures ANOVA (genotype×condition) demonstrated differences in the mean values among the different levels of condition (F = 8.06; p = 0.007). Student's t test indicated that the Mecp2−/y-SC group was significantly different from the other two groups (*: p<0.05).
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pone-0011534-g002: Environmental Enrichment improves neuromotor dysfunction in Mecp2−/y mice.A, Footprint analysis showed impaired walking patterns in Mecp2−/y-SC mice compared with Mecp2−/y-EE and Mecp2+/y−SC control animals. B, Measures taken for footprint analysis .C, Speed of movement (cm/s) was faster for Mecp2−/y-EE than Mecp2−/y-SC mice. D, Mecp2−/y-EE mice displayed improved motor coordination compared with Mecp2−/y-SC evidenced by a shorter time to reach the platform for the first time and E, higher number of arrivals to the platform in the elevated beam test. The total number of animals in each group is shown (n). Mean ± SEM values are presented. A two-way repeated measures ANOVA (genotype×condition) demonstrated differences in the mean values among the different levels of condition (F = 8.06; p = 0.007). Student's t test indicated that the Mecp2−/y-SC group was significantly different from the other two groups (*: p<0.05).

Mentions: To substantiate the home cage observation that Mecp2−/y-EE mice movements were more coordinated than the movements of Mecp2−/y-SC mice, we compared their gait by a footprint analysis (figure 2B). Comparison of the trail of footprints left by Mecp2−/y-EE and Mecp2−/y-SC walking on a straight corridor showed that their stride length and base width was significantly different. Both the hind stride length and hind base width are significantly smaller in Mecp2−/y-EE mice than in Mecp2−/y-SC (N = 4 each genotype; pstride length = 0.053, phind-base width = 0.004; figure 2A). We also analyzed whether EE altered the motor abilities of Mecp2−/y by means of the open field test and the elevated beam test. Evaluation of the novelty-induced locomotor activity on the open field showed that although the total distance travelled by Mecp2−/y-EE and Mecp2−/y-SC was similar (805.7±162.5 and 701.4±124.9 cm for Mecp2−/y-EE and Mecp2−/y-SC, respectively), average displacement speed was significantly faster for Mecp2−/y-EE (42.8±3.5 cm/min) than for Mecp2−/y-SC (36.5±2.1 cm/min). (p = 0.022, figure 2C). These data suggest that there might be some improvement on the neuromotor dysfunction of Mecp2−/y mice on EE conditions. Accordingly, we observed that Mecp2−/y-EE mice outperformed their Mecp2−/y littermates housed in control conditions in the elevated beam test, in which the mice have to walk on an elevated thin wooden dowel to reach the safety of a partially enclosed platform. Mecp2−/y-EE mice reached the platform significantly faster than the control Mecp2−/y mice (figure 2D). In addition, the total number of platform reachings was higher for the Mecp2−/y-EE (figure 2F). Moreover, the performance of enriched Mecp2−/y mice was similar to the performance of Mecp2+/y mice housed either in SC or EE (figure 2D).


Unconventional transcriptional response to environmental enrichment in a mouse model of Rett syndrome.

Kerr B, Silva PA, Walz K, Young JI - PLoS ONE (2010)

Environmental Enrichment improves neuromotor dysfunction in Mecp2−/y mice.A, Footprint analysis showed impaired walking patterns in Mecp2−/y-SC mice compared with Mecp2−/y-EE and Mecp2+/y−SC control animals. B, Measures taken for footprint analysis .C, Speed of movement (cm/s) was faster for Mecp2−/y-EE than Mecp2−/y-SC mice. D, Mecp2−/y-EE mice displayed improved motor coordination compared with Mecp2−/y-SC evidenced by a shorter time to reach the platform for the first time and E, higher number of arrivals to the platform in the elevated beam test. The total number of animals in each group is shown (n). Mean ± SEM values are presented. A two-way repeated measures ANOVA (genotype×condition) demonstrated differences in the mean values among the different levels of condition (F = 8.06; p = 0.007). Student's t test indicated that the Mecp2−/y-SC group was significantly different from the other two groups (*: p<0.05).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2902516&req=5

pone-0011534-g002: Environmental Enrichment improves neuromotor dysfunction in Mecp2−/y mice.A, Footprint analysis showed impaired walking patterns in Mecp2−/y-SC mice compared with Mecp2−/y-EE and Mecp2+/y−SC control animals. B, Measures taken for footprint analysis .C, Speed of movement (cm/s) was faster for Mecp2−/y-EE than Mecp2−/y-SC mice. D, Mecp2−/y-EE mice displayed improved motor coordination compared with Mecp2−/y-SC evidenced by a shorter time to reach the platform for the first time and E, higher number of arrivals to the platform in the elevated beam test. The total number of animals in each group is shown (n). Mean ± SEM values are presented. A two-way repeated measures ANOVA (genotype×condition) demonstrated differences in the mean values among the different levels of condition (F = 8.06; p = 0.007). Student's t test indicated that the Mecp2−/y-SC group was significantly different from the other two groups (*: p<0.05).
Mentions: To substantiate the home cage observation that Mecp2−/y-EE mice movements were more coordinated than the movements of Mecp2−/y-SC mice, we compared their gait by a footprint analysis (figure 2B). Comparison of the trail of footprints left by Mecp2−/y-EE and Mecp2−/y-SC walking on a straight corridor showed that their stride length and base width was significantly different. Both the hind stride length and hind base width are significantly smaller in Mecp2−/y-EE mice than in Mecp2−/y-SC (N = 4 each genotype; pstride length = 0.053, phind-base width = 0.004; figure 2A). We also analyzed whether EE altered the motor abilities of Mecp2−/y by means of the open field test and the elevated beam test. Evaluation of the novelty-induced locomotor activity on the open field showed that although the total distance travelled by Mecp2−/y-EE and Mecp2−/y-SC was similar (805.7±162.5 and 701.4±124.9 cm for Mecp2−/y-EE and Mecp2−/y-SC, respectively), average displacement speed was significantly faster for Mecp2−/y-EE (42.8±3.5 cm/min) than for Mecp2−/y-SC (36.5±2.1 cm/min). (p = 0.022, figure 2C). These data suggest that there might be some improvement on the neuromotor dysfunction of Mecp2−/y mice on EE conditions. Accordingly, we observed that Mecp2−/y-EE mice outperformed their Mecp2−/y littermates housed in control conditions in the elevated beam test, in which the mice have to walk on an elevated thin wooden dowel to reach the safety of a partially enclosed platform. Mecp2−/y-EE mice reached the platform significantly faster than the control Mecp2−/y mice (figure 2D). In addition, the total number of platform reachings was higher for the Mecp2−/y-EE (figure 2F). Moreover, the performance of enriched Mecp2−/y mice was similar to the performance of Mecp2+/y mice housed either in SC or EE (figure 2D).

Bottom Line: RTT is characterized by psychomotor retardation, purposeless hand movements, autistic-like behavior and abnormal gait.We found that EE delayed and attenuated some neurological alterations presented by Mecp2(-/y) mice and prevented the development of motor discoordination and anxiety-related abnormalities.We found that EE induced downregulation of several synaptic markers, suggesting that the partial prevention of RTT-associated phenotypes is achieved through a non-conventional transcriptional program.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, Centro de Estudios Científicos, Valdivia, Chile.

ABSTRACT

Background: Rett syndrome (RTT) is an X-linked postnatal neurodevelopmental disorder caused by mutations in the gene encoding methyl-CpG binding protein 2 (MeCP2) and one of the leading causes of mental retardation in females. RTT is characterized by psychomotor retardation, purposeless hand movements, autistic-like behavior and abnormal gait. We studied the effects of environmental enrichment (EE) on the phenotypic manifestations of a RTT mouse model that lacks MeCP2 (Mecp2(-/y)).

Principal findings: We found that EE delayed and attenuated some neurological alterations presented by Mecp2(-/y) mice and prevented the development of motor discoordination and anxiety-related abnormalities. To define the molecular correlate of this beneficial effect of EE, we analyzed the expression of several synaptic marker genes whose expression is increased by EE in several mouse models.

Conclusions/significance: We found that EE induced downregulation of several synaptic markers, suggesting that the partial prevention of RTT-associated phenotypes is achieved through a non-conventional transcriptional program.

Show MeSH
Related in: MedlinePlus