MOUSE MODEL OF RETARDATION IN DOWNS SYNDROME

描述（由申请人提供）：唐氏综合征（DS）或21三体（Ts 21）是 由21号染色体的三个拷贝的存在引起，并且是最多的 智力迟钝的常见遗传原因。Ts 65 Dn三体小鼠具有 最近被开发，并且是三体的，仅用于鼠的片段 16号染色体与人类21号染色体的片段同源， 导致智力迟钝和易患阿尔茨海默病， DS.这只小鼠表现出异常行为， 学习范式我们证明了长时程增强（LTP）和长时程增强（LTP）的作用。 在海马CA 1区，长时程抑制（LTD）分别减少和增加， Ts 65 Dn小鼠海马区。本提案的目的是 寻找导致异常LTP和LTD的机制。三个具体目标是 建议测试异常LTP和LTD是由于信号变化引起的 由蛋白激酶A（PKA）和/或蛋白激酶 C（PKC），可引起电压依赖性Na+的翻译后变化， Ca 2+通道和NMDA-，AMPA-谷氨酸受体，并引起突触的变化， 海马体的活动。目的#1：测定Ts 65 Dn中的PKA途径活性 海马与LTP和LTD范式的关系。确定表达式 磷酸化CREB。目的#2：Ts 65 Dn海马中的PKC活性与 LTP和LTD范式。确定PKC亚型的表达模式。目的 #3：确定电压的表达和翻译后修饰 依赖性Na+，Ca 2+通道和NMDA -，AMPA-谷氨酸受体， 有核膜片钳记录技术和结合研究。的影响 将在永久性过度表达Na+的细胞系中检测PKC亚型 通道、Ca ~（2+）通道、NMDA和AMPA受体。信号转导 DS遗传模型中的损伤将决定 治疗精神发育迟滞。此外，这项研究的结果将 包括进一步了解PKA和PKC的作用以及电压依赖性 通道和NMDA-和AMPA-受体的机制，是背后的LTP和 公司

DESCRIPTION (Provided by applicant): Down syndrome (DS) or trisomy 21 (Ts21) is caused by the presence of three copies of chromosome 21, and is the most frequent genetic cause of mental retardation. The Ts65Dn trisomic mouse has recently been developed and is trisomic only for the segment of murine chromosome 16 that is homologous to the segment of human chromosome 21 thought to contribute to mental retardation and vulnerability to Alzheimer disease in DS. This mouse demonstrates abnormal behavior and is impaired in various learning paradigms. We demonstrated that long-term potentiation (LTP) and long- term depression (LTD) decrease and increase respectively in the CAl region of the Ts65Dn mouse of Ts65Dn mouse hippocampus. The objective of this proposal is to find mechanisms that cause the abnormal LTP and LTD. Three specific aims are proposed to test that abnormal LTP and LTD are due to changes in signal transduction pathways mediated by protein kinase A (PKA) and/or protein kinase C (PKC) that would cause posttranslational changes in voltage-dependent Na+, Ca2+ channels and NMDA-, AMPA-glutamate receptors and cause changes in synaptic activity in the hippocampus. Aim#1: Determine PKA pathway activity in Ts65Dn hippocampus in relation to LTP and LTD paradigm. Determine expression of phosphorylated CREB. Aim #2:PKC activity in Ts65Dn hippocampus in relation to LTP and LTD paradigm. Determine expression pattern of PKC isoforms. Aim #3:Determine the expression and posttranslational modification of voltage dependent Na+, Ca2+ channels and NMDA -, AMPA- glutamate receptors using nucleated patch-clamp recording technique and binding studies. The impact of PKC isoforms will be tested in cell lines that permanently over express Na+ channel, Ca2+ channels, NMDA and AMPA receptors. Signal transduction impairments in genetic model of DS will determine important targets for treatment of mental retardation. In addition the outcome of this research will include further understanding of the role of PKA and PKC and voltage-dependent channels and NMDA- and AMPA-receptors in the mechanisms that are behind LTP and LTD.