Protein dynamics associated with failed and rescued learning in the Ts65Dn mouse model of Down syndrome.
Protein dynamics associated with failed and rescued learning in the Ts65Dn mouse model of Down syndrome.
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DOI：
10.1371/journal.pone.0119491
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Gardiner KJ
中科院分区：
文献类型：
--
作者：
Ahmed MM;Dhanasekaran AR;Block A;Tong S;Costa AC;Stasko M;Gardiner KJ
唐氏综合症 (DS) 是由人类 21 号染色体 (Hsa21) 的额外副本引起的。尽管它是智力障碍 (ID) 最常见的遗传原因，但迄今为止尚无有效的药物疗法。 DS 的 Ts65Dn 小鼠模型是约 55% Hsa21 经典蛋白质编码基因的直系同源物。这些小鼠表现出许多与 DS 相关的特征，包括需要功能性海马体的学习和记忆 (L/M) 任务的缺陷。最近，N-甲基-D-天冬氨酸 (NMDA) 受体拮抗剂美金刚被证明可以在多项 L/M 任务中挽救 Ts65Dn 的性能。然而，这些研究并未伴随分子分析。在之前的工作中，我们描述了对照小鼠暴露于情境恐惧调节（CFC）后，无论是否接受美金刚治疗，海马和皮层中诱导的蛋白质表达变化。在这里，我们将此分析扩展到 Ts65Dn 小鼠，测量 CFC 学习失败和美金刚挽救学习后 Ts65Dn 小鼠皮质和海马中 85 种蛋白质/蛋白质修饰的水平，包括 MAP 激酶和 MTOR 通路的成分以及 NMDA 受体的亚基。我们发现，与野生型同窝对照小鼠相比，（i）在正常学习中对照小鼠中观察到的动态反应中，超过 40% 也发生在学习失败的 Ts65Dn 中，或者通过基线异常进行补偿，因此被认为是成功学习所必需的，但还不够；（ii）美金刚治疗通常不会使初始蛋白质水平正常化，而是在测量和测量的大约一半蛋白质中诱导直接和间接反应。 导致终点蛋白质水平正常化。这些数据集共同提供了与 Ts65Dn 中学习的药理学救援相关的复杂性的第一视角。将此类研究扩展到其他药物和 DS 小鼠模型将有助于确定有效临床试验的药物疗法。
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.
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DOI：
10.1177/0269881111405366
发表时间：
2011-08
期刊：
Journal of psychopharmacology (Oxford, England)
影响因子：
--
作者：
Braudeau J;Delatour B;Duchon A;Pereira PL;Dauphinot L;de Chaumont F;Olivo-Marin JC;Dodd RH;Hérault Y;Potier MC
通讯作者：
Potier MC
影响因子：
2.7
作者：
Chang, Qing;Gold, Paul E.
通讯作者：
Gold, Paul E.
识别TS65DN和TS1CJE鼠标线中的易位断点：与唐氏综合症建模的相关性。
影响因子：
2.5
作者：
Duchon, Arnaud;Raveau, Matthieu;Chevalier, Claire;Nalesso, Valerie;Sharp, Andrew J.;Herault, Yann
通讯作者：
Herault, Yann
DOI：
10.1124/jpet.105.085142
发表时间：
2005-09-01
影响因子：
3.5
作者：
Chen, HSV;Lipton, SA
通讯作者：
Lipton, SA
影响因子：
7
作者：
Ahmed, Md. Mahiuddin;Dhanasekaran, A. Ranjitha;Gardiner, Katheleen J.
通讯作者：
Gardiner, Katheleen J.