MAP Kinase Analysis in a Mouse Model of Down Syndrome

在唐氏综合征患者和唐氏综合征Ts 65 Dn小鼠模型中，可以看到基底前脑内侧隔神经元（MSN）中胆碱能标记物的缺失和基于海马的任务的表现缺陷，这些神经元向海马提供胆碱能输入。我们推测MAP激酶信号通路的异常与神经元标记物的缺失和缺失有关。这一假说得到了以下观察结果的支持：神经生长因子（NGF）在Ts 65 Dn小鼠海马和内侧隔胆碱能神经元中的浓度和分布发生了改变，NGF通过内吞作用和MAPK信号传导发挥作用， 21号染色体基因Intersectin 1（ITSN 1）、synaptojanin 1（SYNJ 1）、一过性淋巴瘤和转移瘤1（TIAM 1）、双特异性激酶1A（DYRK 1A）和β-淀粉样前体蛋白（APP）与内吞作用、MAPK信号传导途径或下游基因转录的组分相互作用和/或直接影响内吞作用、MAPK信号传导途径或下游基因转录。重要的是，我们的初步数据显示了Ts 65 Dn小鼠中MAPK通路的异常。通过将实验集中在与认知功能相关的通路上，可以最好地实现对这个复杂系统的理解。为此，我们建议 具体目标如下：（2）通过测量上游MAPK组分发动蛋白、Ras、Rac和Akt的活化水平来评估目的（1）中发现的异常的来源，所述上游MAPK组分发动蛋白、Ras、Rac和Akt中的每一种均受一种或多种21号染色体蛋白的影响;和（3）测量MAPK靶、Creb、Sos和CHAT的活化水平。这些目标的实现将确定方向和异常的程度，在已知的途径是相关的基于校园的学习。我们建议将这项工作作为RO 3，以建立我们在这一领域的专业知识，并描述 Ts 65 Dn小鼠中的MAP激酶途径异常。该试点项目的结果将指导未来对潜在遗传机制、药理学操作的可能性以及该途径异常的行为和认知后果的研究。

Deficits in performance of hippocampal-based tasks and loss of cholinergic markers in the medial septal neurons (MSN) in the basal forebrain that supply cholinergic input to the hippocampus are seen in individuals with Down syndrome and in the Ts65Dn mouse model of Down syndrome. We hypothesize that abnormalities in the MAP Kinase signaling pathway are relevant to the deficits and to the loss of neuronal markers. This hypothesis is supported by observations that the concentration and distribution of nerve growth factor (NGF) is altered in the hippocampus and the medial septal cholinergic neurons of the Ts65Dn mice, that NGF functions through endocytosis and MAPK signaling, that hippocampal deficits can be caused by MAPK signaling defects, and that the chromosome 21 genes Intersectin 1 (ITSN1), synaptojanin 1 (SYNJ1), transient lymphoma and metastasis 1 (TIAM1), dual specificity kinase 1A (DYRK1A), and beta-amyloid precursor protein (APP) interact with and/or directly affect components of endocytosis, MAPK signaling pathways or downstream gene transcription. Importantly, our preliminary data show abnormalities of the MAPK pathway in Ts65Dn mice. Substantial gains in understanding this complex system can best be achieved by focusing experiments on a pathway relevant to cognitive function. To do this, we propose the following specific aims: (1) to assess MAPK activity in the hippocampus of Ts65Dn mice by measuring levels of phosphorylated protein or kinase activity of pathway endpoints Erk1, Erk2, Erk5 and Jnk; (2) to evaluate [he source of abnormalities found in aim (1) by measuring activation levels of upstream MAPK components dynamin, Ras, Rac and Akt, each of which is affected by one or more of the chromosome 21 proteins; and (3) measuring levels of activation of MAPK targets, Creb, Sos and CHAT. Fulfillment of these aims will define the direction and magnitude of abnormalities in a pathway known to be relevant to hippocampal-based learning. We propose this work as an RO3 to establish our expertise in this area and to describe the extent of MAP Kinase pathway abnormalities in the Ts65Dn mouse. Results from this pilot project will direct future studies of the underlying genetic mechanisms, possibilities for pharmacological manipulation, and behavioral and cognitive consequences of abnormalities in this pathway.