Restoring synaptic function in Down Syndrome mice

恢复唐氏综合症小鼠的突触功能

• 批准号: 9340289
• 负责人: K. Ulrich Bayer
• 金额: $ 23.33万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9340289
• 关键词: Adverse effects; Angelman Syndrome; Behavior; Behavioral; Biological Markers; Brain; Breeding; Chronic; Cognitive; Cognitive deficits; Communication; Complex; Crossbreeding; Down Syndrome; Functional disorder; Future; Genetic; Glutamates; Goals; Hereditary Disease; Impaired cognition; Impairment; Intervention; Knock-in Mouse; Lead; Learning; Long-Term Depression; Long-Term Potentiation; Memory; Mental Depression; Modeling; Molecular; Mus; Mutant Strains Mice; Mutation; Neurotransmitters; Nitric Oxide; Patients; Pharmacological Treatment; Pharmacology; Phosphorylation; Publishing; Reactive Oxygen Species; Regimen; Synapses; Synaptic plasticity; Syndrome; System; Testing; Therapeutic; Treatment Protocols; Work; antioxidant therapy; brain cell; calmodulin-dependent protein kinase II; cognitive function; fear memory; genetic approach; improved; insight; mouse model; novel; novel therapeutic intervention; novel therapeutics; oxidation; restoration; screening; success; synaptic function; tool; transmission process; unpublished works

Project Summary Down Syndrome (DS) model mice have three abnormalities in synaptic functions that can explain the cognitive deficits in DS: Decreased long-term potentiation (LTP) and enhanced long- term depression (LTD) of glutamatergic synapses, as well as enhanced inhibitory transmission at GABAergic synapses. Our recent published work indicates that all three observed synaptic dysfunction should be caused by the hyper-phosphorylation of the Ca2+/calmodulin-dependent protein kinase II (CaMKII) seen in DS mice. Our recent unpublished work indicates an intriguing possible mechanism for the cause of CaMKII hyper-phosphorylation in the DS mice. Importantly, this mechanism could also be targeted by pharmacological intervention. As a proof of principle, this project will focus on two aspects of the overall question: (Aim 1) Testing the underlying cause for CaMKII hyper-phosphorylation in DS mice (using a new mutant mouse line that has been generated in the lab and that is incompetent for the proposed underlying mechanism); (Aim 2) Restoration of normal LTP by genetic reversal of T305/306 hyper-phosphorylation in DS mice (using a CaMKII T305/306AV mutant mouse line currently available to the lab). Future studies will test restoration of the other synaptic dysfunctions in DS, restoration of cognitive behavioral tasks, and restoration also by pharmacological means. Notably, while it may seem preposterous to propose a reversal of cognitive impairments in a very complex syndrome by a rather simple intervention, there is actually prior precedent for success: In a model of a different genetic condition that causes cognitive impairments, Angelman Syndrome (AS), CaMKII is also hyper-phosphorylated, and even heterozygous T305/306AV mutation was sufficient to restore both normal LTP and spatial learning. In contrast to AS, the hyper-phosphorylation of CaMKII in DS could be targeted also pharmacologically (if our hypothesized underlying mechanism is correct). Thus, this project will not only provide significant further insight into the mechanism underlying normal synaptic functions and their impairments in DS, but also has tremendous potential for directly opening a new therapeutic avenue for restoring cognitive functions in patients with DS.

项目摘要 唐氏综合症（DS）模型小鼠在突触功能中具有三种异常 解释DS中的认知缺陷：长期增强（LTP）的降低并增强了长期 谷氨酸能突触的术语抑郁（LTD），并增强了抑制性传播 在GABA能突触。我们最近发表的工作表明，这三个观察到了突触 功能障碍应由Ca2+/钙调蛋白依赖性的高磷酸化引起 蛋白激酶II（CAMKII）在DS小鼠中看到。我们最近未发表的工作表明 DS小鼠中CAMKII高磷酸化原因的可能机制。 重要的是，该机制也可以通过药理学干预来针对。 作为原则的证明，该项目将重点介绍总体问题的两个方面： （AIM 1）测试DS小鼠中CaMKII高磷酸化的根本原因（使用A 在实验室中生成的新型突变鼠系，对于 提出的潜在机制）； （AIM 2）通过T305/306在遗传逆转中恢复正常LTP。 DS小鼠（使用当前可用于实验室可用的CAMKII T305/306AV突变鼠标线）。 未来的研究将测试DS中其他突触功能障碍的恢复，恢复 认知行为任务和药理手段的恢复。 值得注意的是，虽然提出对认知障碍的逆转似乎是荒谬的 非常简单的干预措施非常复杂的综合征，实际上有先前的先例 成功：在导致认知障碍的不同遗传条件的模型中， Angelman综合征（AS），Camkii也被过度磷酸化，甚至是杂合子 T305/306AV突变足以恢复正常的LTP和空间学习。在 与AS形成鲜明对比的是，CaMKII在DS中的高磷酸化也可以针对 在药理学上（如果我们假设的潜在机制是正确的）。因此，这个项目将 不仅可以进一步了解正常突触的基础机制 功能及其在DS中的损害，但也具有直接打开的巨大潜力 用于恢复DS患者认知功能的新治疗途径。