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

Patterns of protein responses: abnormal in baseline and NL = 0.(a), (b), normalized in FL and RL + B-tm; (c), (d), normalized in RL + B-tm only. For abbreviations see Fig. 2.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0119491.g004: Patterns of protein responses: abnormal in baseline and NL = 0.(a), (b), normalized in FL and RL + B-tm; (c), (d), normalized in RL + B-tm only. For abbreviations see Fig. 2.

Mentions: Additional patterns involve proteins that do not change in NL but that are abnormal in B. As shown in Fig. 4, some of the abnormalities in B are compensated by changes in both FL and RL or in FL and in B-tm (e.g. AKT and pRSK in the hippocampus nuclear and cytosolic fraction, respectively (Fig. 4A,B)). In other cases, compensatory responses do not occur in FL, but are induced indirectly in RL, e.g. pPKCG in the cortex cytosol, or directly by memantine, e.g. NUMB in the cortex membrane fraction (Fig. 4C,D). The data in Fig. 4C,D again suggest that these abnormalities in B may contribute to learning impairment in untreated Ts65Dn.


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)

Patterns of protein responses: abnormal in baseline and NL = 0.(a), (b), normalized in FL and RL + B-tm; (c), (d), normalized in RL + B-tm only. For abbreviations see Fig. 2.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0119491.g004: Patterns of protein responses: abnormal in baseline and NL = 0.(a), (b), normalized in FL and RL + B-tm; (c), (d), normalized in RL + B-tm only. For abbreviations see Fig. 2.
Mentions: Additional patterns involve proteins that do not change in NL but that are abnormal in B. As shown in Fig. 4, some of the abnormalities in B are compensated by changes in both FL and RL or in FL and in B-tm (e.g. AKT and pRSK in the hippocampus nuclear and cytosolic fraction, respectively (Fig. 4A,B)). In other cases, compensatory responses do not occur in FL, but are induced indirectly in RL, e.g. pPKCG in the cortex cytosol, or directly by memantine, e.g. NUMB in the cortex membrane fraction (Fig. 4C,D). The data in Fig. 4C,D again suggest that these abnormalities in B may contribute to learning impairment in untreated Ts65Dn.

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