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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 on Mecp2−/y-EE mice induces a decrease in the expression of a set of synaptic plasticity-related genes.A, A significant difference in the steady-state level of mRNA for Syp, PSD95 and SGK-1 was observed in hypothalamus of Mecp2−/y-EE in comparison with in Mecp2−/y-SC mice assessed by qRT-PCR. Syp WT: The expected EE-induced increase in Syp in Mecp2+/y-EE (normalized to Mecp2+/y-SC) is shown as a darker bar. B, In samples from cerebral cortex, differences were detected in Syt9, Stx1a and SGK-1. The results are expressed as percentage of the Mecp2−/y-SC control group. * p<0.05 by Student's test (n = 5 for each group).
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pone-0011534-g004: Environmental Enrichment on Mecp2−/y-EE mice induces a decrease in the expression of a set of synaptic plasticity-related genes.A, A significant difference in the steady-state level of mRNA for Syp, PSD95 and SGK-1 was observed in hypothalamus of Mecp2−/y-EE in comparison with in Mecp2−/y-SC mice assessed by qRT-PCR. Syp WT: The expected EE-induced increase in Syp in Mecp2+/y-EE (normalized to Mecp2+/y-SC) is shown as a darker bar. B, In samples from cerebral cortex, differences were detected in Syt9, Stx1a and SGK-1. The results are expressed as percentage of the Mecp2−/y-SC control group. * p<0.05 by Student's test (n = 5 for each group).

Mentions: Mecp2−/y mice subjected to tests designed to measure anxiety levels exhibit a behavior consistent with decreased anxiety (see [7] and [26]). Notably, the behavior of the Mecp2−/y-EE and Mecp2−/y-SC on the elevated plus maze was significantly different (figure 3). As anticipated by previous reports [7], [26], Mecp2−/y-SC mice did not show a preference for the safety of the closed arms of the maze as wild type mice do. On the contrary, Mecp2−/y-SC mice spent significantly more time in the open than in the closed arms (figure 3A). However, if the Mecp2−/y were housed in an enriched environment, their preference for the open arms disappears (figure 3A). These results indicate that EE prevents the development of this phenotype. To rule out that EE resulted in a stressful condition that increased the levels of anxiety of Mecp2−/y mice, we measured the expression of Crh, a key regulator of the mammalian stress response. We found that the expression of Crh in hypothalamus was similar in Mecp2−/y-EE and Mecp2−/y-SC mice (figure 4A), suggesting that the restoration of a normal behavior on the plus maze induced by EE in Mecp2−/y mice is not just a consequence of elevated stress. Since mice of the 129 genetic background are not very good responders in the plus maze test [27], as evidenced by the behavior of the Mecp2+/y-SC on this test (figure 3A), we decided to repeat this particular test on a B6129 F1 background. In this genetic background, the preference of Mecp2+/y-SC for the closed arms of the maze was more pronounced. Again, Mecp2−/y-SC did not show a preference for the closed arms of the maze, but Mecp2−/y-EE mice exhibited a behavior indistinguishable from their wild type littermates (figure 3B), further confirming the positive effect of EE on the plus maze phenotype of the Mecp2−/y mice. Motor performance of the Mecp2−/y mice was also improved by EE in this background (data not shown)


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 on Mecp2−/y-EE mice induces a decrease in the expression of a set of synaptic plasticity-related genes.A, A significant difference in the steady-state level of mRNA for Syp, PSD95 and SGK-1 was observed in hypothalamus of Mecp2−/y-EE in comparison with in Mecp2−/y-SC mice assessed by qRT-PCR. Syp WT: The expected EE-induced increase in Syp in Mecp2+/y-EE (normalized to Mecp2+/y-SC) is shown as a darker bar. B, In samples from cerebral cortex, differences were detected in Syt9, Stx1a and SGK-1. The results are expressed as percentage of the Mecp2−/y-SC control group. * p<0.05 by Student's test (n = 5 for each group).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2902516&req=5

pone-0011534-g004: Environmental Enrichment on Mecp2−/y-EE mice induces a decrease in the expression of a set of synaptic plasticity-related genes.A, A significant difference in the steady-state level of mRNA for Syp, PSD95 and SGK-1 was observed in hypothalamus of Mecp2−/y-EE in comparison with in Mecp2−/y-SC mice assessed by qRT-PCR. Syp WT: The expected EE-induced increase in Syp in Mecp2+/y-EE (normalized to Mecp2+/y-SC) is shown as a darker bar. B, In samples from cerebral cortex, differences were detected in Syt9, Stx1a and SGK-1. The results are expressed as percentage of the Mecp2−/y-SC control group. * p<0.05 by Student's test (n = 5 for each group).
Mentions: Mecp2−/y mice subjected to tests designed to measure anxiety levels exhibit a behavior consistent with decreased anxiety (see [7] and [26]). Notably, the behavior of the Mecp2−/y-EE and Mecp2−/y-SC on the elevated plus maze was significantly different (figure 3). As anticipated by previous reports [7], [26], Mecp2−/y-SC mice did not show a preference for the safety of the closed arms of the maze as wild type mice do. On the contrary, Mecp2−/y-SC mice spent significantly more time in the open than in the closed arms (figure 3A). However, if the Mecp2−/y were housed in an enriched environment, their preference for the open arms disappears (figure 3A). These results indicate that EE prevents the development of this phenotype. To rule out that EE resulted in a stressful condition that increased the levels of anxiety of Mecp2−/y mice, we measured the expression of Crh, a key regulator of the mammalian stress response. We found that the expression of Crh in hypothalamus was similar in Mecp2−/y-EE and Mecp2−/y-SC mice (figure 4A), suggesting that the restoration of a normal behavior on the plus maze induced by EE in Mecp2−/y mice is not just a consequence of elevated stress. Since mice of the 129 genetic background are not very good responders in the plus maze test [27], as evidenced by the behavior of the Mecp2+/y-SC on this test (figure 3A), we decided to repeat this particular test on a B6129 F1 background. In this genetic background, the preference of Mecp2+/y-SC for the closed arms of the maze was more pronounced. Again, Mecp2−/y-SC did not show a preference for the closed arms of the maze, but Mecp2−/y-EE mice exhibited a behavior indistinguishable from their wild type littermates (figure 3B), further confirming the positive effect of EE on the plus maze phenotype of the Mecp2−/y mice. Motor performance of the Mecp2−/y mice was also improved by EE in this background (data not shown)

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