Limits...
Protein dynamics associated with failed and rescued learning in the Ts65Dn mouse model of Down syndrome.

Ahmed MM, Dhanasekaran AR, Block A, Tong S, Costa AC, Stasko M, Gardiner KJ - PLoS ONE (2015)

Bottom Line: These studies, however, have not been accompanied by molecular analyses.We show that, compared with wild type littermate controls, (i) of the dynamic responses seen in control mice in normal learning, >40% also occur in Ts65Dn in failed learning or are compensated by baseline abnormalities, and thus are considered necessary but not sufficient for successful learning, and (ii) treatment with memantine does not in general normalize the initial protein levels but instead induces direct and indirect responses in approximately half the proteins measured and results in normalization of the endpoint protein levels.Together, these datasets provide a first view of the complexities associated with pharmacological rescue of learning in the Ts65Dn.

View Article: PubMed Central - PubMed

Affiliation: Linda Crnic Institute for Down Syndrome, Department of Pediatrics, University of Colorado Denver, Mail Stop 8608, 12700 E 19th Avenue, Aurora, Colorado 80045, United States of America.

ABSTRACT
Down syndrome (DS) is caused by an extra copy of human chromosome 21 (Hsa21). Although it is the most common genetic cause of intellectual disability (ID), there are, as yet, no effective pharmacotherapies. The Ts65Dn mouse model of DS is trisomic for orthologs of ∼55% of Hsa21 classical protein coding genes. These mice display many features relevant to those seen in DS, including deficits in learning and memory (L/M) tasks requiring a functional hippocampus. Recently, the N-methyl-D-aspartate (NMDA) receptor antagonist, memantine, was shown to rescue performance of the Ts65Dn in several L/M tasks. These studies, however, have not been accompanied by molecular analyses. In previous work, we described changes in protein expression induced in hippocampus and cortex in control mice after exposure to context fear conditioning (CFC), with and without memantine treatment. Here, we extend this analysis to Ts65Dn mice, measuring levels of 85 proteins/protein modifications, including components of MAP kinase and MTOR pathways, and subunits of NMDA receptors, in cortex and hippocampus of Ts65Dn mice after failed learning in CFC and after learning was rescued by memantine. We show that, compared with wild type littermate controls, (i) of the dynamic responses seen in control mice in normal learning, >40% also occur in Ts65Dn in failed learning or are compensated by baseline abnormalities, and thus are considered necessary but not sufficient for successful learning, and (ii) treatment with memantine does not in general normalize the initial protein levels but instead induces direct and indirect responses in approximately half the proteins measured and results in normalization of the endpoint protein levels. Together, these datasets provide a first view of the complexities associated with pharmacological rescue of learning in the Ts65Dn. Extending such studies to additional drugs and mouse models of DS will aid in identifying pharmacotherapies for effective clinical trials.

No MeSH data available.


Related in: MedlinePlus

Relationships among pairwise group comparisons.Eight groups of mice, control and Ts65Dn, not trained in CFC (SC, shock context) and trained in CFC (CS, context shock), injected with either saline or memantine, were generated. The four SC groups represent baseline (B) conditions and are shown in rectangles in the lower part of the figure. Three CS groups are shown in hexagons. Lines connecting groups indicate the nine pairwise comparisons of biological interest that are discussed here. Each comparison is labelled with the complete name and the abbreviated name used in the text. Summary data for all comparisons, except B-cm, are presented in Table 2 (for B-cm data, see reference 39). *, comparisons analyzed for data shown in Figs. 2–7. See Table 1 for additional information.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4368539&req=5

pone.0119491.g001: Relationships among pairwise group comparisons.Eight groups of mice, control and Ts65Dn, not trained in CFC (SC, shock context) and trained in CFC (CS, context shock), injected with either saline or memantine, were generated. The four SC groups represent baseline (B) conditions and are shown in rectangles in the lower part of the figure. Three CS groups are shown in hexagons. Lines connecting groups indicate the nine pairwise comparisons of biological interest that are discussed here. Each comparison is labelled with the complete name and the abbreviated name used in the text. Summary data for all comparisons, except B-cm, are presented in Table 2 (for B-cm data, see reference 39). *, comparisons analyzed for data shown in Figs. 2–7. See Table 1 for additional information.

Mentions: A standard protocol for CFC requires two groups of mice, the SC (shock-context) group that does not learn the context and the CS (context-shock) group that should learn. For the experiments here, one half of each of the SC and CS groups of mice were injected with saline and the other half, with memantine. Thus, for the two genotypes, control and trisomic, there are a total of 8 groups of mice. Differences due to genotype and changes caused by treatment were determined by pairwise group comparisons. Twenty-eight pairwise comparisons can be done but only a subset of these are of biological interest. Fig. 1 illustrates the relationships between groups that form the subset of comparisons discussed here. The nomenclature is complicated and listed for reference in Table 1. Four comparisons concern initial conditions: B (baseline; Ts65Dn-saline vs. control-saline, t-SC-s vs. c-SC-s) identifies initial abnormalities in the Ts65Dn relative to controls when neither is trained in CFC; B-tm (baseline Ts65Dn treated with memantine) and B-cm (baseline control treated with memantine) identify changes in the initial protein profiles (SC-m vs. SC-s) in Ts65Dn and control mice, respectively, caused by memantine treatment alone, and B-tm-cs (Ts65Dn treated with memantine vs. controls treated with saline, t-SC-m vs. c-SC-s) shows how well or poorly memantine treatment normalizes the baseline, initial, Ts65Dn profile. Three comparisons represent changes associated with stimulation to learn: NL (normal learning in control mice; c-CS-s vs. c-SC-s), FL (failed learning in Ts65Dn mice; t-CS-s vs. t-SC-s), and RL (rescued learning in Ts65Dn mice; t-CS-m vs. t-SC-m). Lastly, two comparisons represent “end points”: RL-FL (t-CS-m vs. t-CS-s) identifies differences in the final profiles between rescued and failed learning in the Ts65Dn mice and RL-NL (t-CS-m vs. c-CS-s) identifies how well, or poorly, profiles in rescued learning in the Ts65Dn resemble those in normal learning in control mice. Two of these comparisons, NL and B-cm, were reported previously and are included here for ease of comparison.


Protein dynamics associated with failed and rescued learning in the Ts65Dn mouse model of Down syndrome.

Ahmed MM, Dhanasekaran AR, Block A, Tong S, Costa AC, Stasko M, Gardiner KJ - PLoS ONE (2015)

Relationships among pairwise group comparisons.Eight groups of mice, control and Ts65Dn, not trained in CFC (SC, shock context) and trained in CFC (CS, context shock), injected with either saline or memantine, were generated. The four SC groups represent baseline (B) conditions and are shown in rectangles in the lower part of the figure. Three CS groups are shown in hexagons. Lines connecting groups indicate the nine pairwise comparisons of biological interest that are discussed here. Each comparison is labelled with the complete name and the abbreviated name used in the text. Summary data for all comparisons, except B-cm, are presented in Table 2 (for B-cm data, see reference 39). *, comparisons analyzed for data shown in Figs. 2–7. See Table 1 for additional information.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4368539&req=5

pone.0119491.g001: Relationships among pairwise group comparisons.Eight groups of mice, control and Ts65Dn, not trained in CFC (SC, shock context) and trained in CFC (CS, context shock), injected with either saline or memantine, were generated. The four SC groups represent baseline (B) conditions and are shown in rectangles in the lower part of the figure. Three CS groups are shown in hexagons. Lines connecting groups indicate the nine pairwise comparisons of biological interest that are discussed here. Each comparison is labelled with the complete name and the abbreviated name used in the text. Summary data for all comparisons, except B-cm, are presented in Table 2 (for B-cm data, see reference 39). *, comparisons analyzed for data shown in Figs. 2–7. See Table 1 for additional information.
Mentions: A standard protocol for CFC requires two groups of mice, the SC (shock-context) group that does not learn the context and the CS (context-shock) group that should learn. For the experiments here, one half of each of the SC and CS groups of mice were injected with saline and the other half, with memantine. Thus, for the two genotypes, control and trisomic, there are a total of 8 groups of mice. Differences due to genotype and changes caused by treatment were determined by pairwise group comparisons. Twenty-eight pairwise comparisons can be done but only a subset of these are of biological interest. Fig. 1 illustrates the relationships between groups that form the subset of comparisons discussed here. The nomenclature is complicated and listed for reference in Table 1. Four comparisons concern initial conditions: B (baseline; Ts65Dn-saline vs. control-saline, t-SC-s vs. c-SC-s) identifies initial abnormalities in the Ts65Dn relative to controls when neither is trained in CFC; B-tm (baseline Ts65Dn treated with memantine) and B-cm (baseline control treated with memantine) identify changes in the initial protein profiles (SC-m vs. SC-s) in Ts65Dn and control mice, respectively, caused by memantine treatment alone, and B-tm-cs (Ts65Dn treated with memantine vs. controls treated with saline, t-SC-m vs. c-SC-s) shows how well or poorly memantine treatment normalizes the baseline, initial, Ts65Dn profile. Three comparisons represent changes associated with stimulation to learn: NL (normal learning in control mice; c-CS-s vs. c-SC-s), FL (failed learning in Ts65Dn mice; t-CS-s vs. t-SC-s), and RL (rescued learning in Ts65Dn mice; t-CS-m vs. t-SC-m). Lastly, two comparisons represent “end points”: RL-FL (t-CS-m vs. t-CS-s) identifies differences in the final profiles between rescued and failed learning in the Ts65Dn mice and RL-NL (t-CS-m vs. c-CS-s) identifies how well, or poorly, profiles in rescued learning in the Ts65Dn resemble those in normal learning in control mice. Two of these comparisons, NL and B-cm, were reported previously and are included here for ease of comparison.

Bottom Line: These studies, however, have not been accompanied by molecular analyses.We show that, compared with wild type littermate controls, (i) of the dynamic responses seen in control mice in normal learning, >40% also occur in Ts65Dn in failed learning or are compensated by baseline abnormalities, and thus are considered necessary but not sufficient for successful learning, and (ii) treatment with memantine does not in general normalize the initial protein levels but instead induces direct and indirect responses in approximately half the proteins measured and results in normalization of the endpoint protein levels.Together, these datasets provide a first view of the complexities associated with pharmacological rescue of learning in the Ts65Dn.

View Article: PubMed Central - PubMed

Affiliation: Linda Crnic Institute for Down Syndrome, Department of Pediatrics, University of Colorado Denver, Mail Stop 8608, 12700 E 19th Avenue, Aurora, Colorado 80045, United States of America.

ABSTRACT
Down syndrome (DS) is caused by an extra copy of human chromosome 21 (Hsa21). Although it is the most common genetic cause of intellectual disability (ID), there are, as yet, no effective pharmacotherapies. The Ts65Dn mouse model of DS is trisomic for orthologs of ∼55% of Hsa21 classical protein coding genes. These mice display many features relevant to those seen in DS, including deficits in learning and memory (L/M) tasks requiring a functional hippocampus. Recently, the N-methyl-D-aspartate (NMDA) receptor antagonist, memantine, was shown to rescue performance of the Ts65Dn in several L/M tasks. These studies, however, have not been accompanied by molecular analyses. In previous work, we described changes in protein expression induced in hippocampus and cortex in control mice after exposure to context fear conditioning (CFC), with and without memantine treatment. Here, we extend this analysis to Ts65Dn mice, measuring levels of 85 proteins/protein modifications, including components of MAP kinase and MTOR pathways, and subunits of NMDA receptors, in cortex and hippocampus of Ts65Dn mice after failed learning in CFC and after learning was rescued by memantine. We show that, compared with wild type littermate controls, (i) of the dynamic responses seen in control mice in normal learning, >40% also occur in Ts65Dn in failed learning or are compensated by baseline abnormalities, and thus are considered necessary but not sufficient for successful learning, and (ii) treatment with memantine does not in general normalize the initial protein levels but instead induces direct and indirect responses in approximately half the proteins measured and results in normalization of the endpoint protein levels. Together, these datasets provide a first view of the complexities associated with pharmacological rescue of learning in the Ts65Dn. Extending such studies to additional drugs and mouse models of DS will aid in identifying pharmacotherapies for effective clinical trials.

No MeSH data available.


Related in: MedlinePlus