Restoring synaptic function in Down Syndrome mice

恢复唐氏综合症小鼠的突触功能

基本信息

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
项目类别：
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intervention novel therapeutics oxidation restoration screening success synaptic function tool transmission process unpublished works

项目摘要

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 Our recent unpublished work indicates an intriguing possible mechanism for the cause of CaMKII hyper-phosphorylation in the DS mice.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.

项目概要唐氏综合症（DS）模型小鼠的突触功能存在三种异常，解释 DS 中的认知缺陷：长时程增强 (LTP) 降低和长时程增强谷氨酸能突触的术语抑制（LTD）以及增强的抑制传递在 GABA 能突触处。我们最近发表的工作表明，所有三个观察到的突触功能障碍应该是由 Ca2+/钙调蛋白依赖的过度磷酸化引起的 DS 小鼠中发现蛋白激酶 II (CaMKII)。我们最近未发表的工作表明 DS 小鼠中 CaMKII 过度磷酸化的有趣可能机制。重要的是，这种机制也可以通过药物干预来靶向。作为原理证明，该项目将重点关注整个问题的两个方面：（目标 1）测试 DS 小鼠 CaMKII 过度磷酸化的根本原因（使用实验室中产生的新突变小鼠品系，无法胜任拟议的基本机制）；（目标 2）通过 T305/306 过度磷酸化的基因逆转恢复正常 LTP DS 小鼠（使用实验室目前可用的 CaMKII T305/306AV 突变小鼠系）。未来的研究将测试 DS 中其他突触功能障碍的恢复，认知行为任务，也可以通过药理学手段恢复。值得注意的是，虽然提出逆转认知障碍似乎很荒谬通过相当简单的干预来实现非常复杂的综合症，实际上有先例成功：在导致认知障碍的不同遗传条件模型中， Angelman综合症（AS），CaMKII也是过度磷酸化的，甚至是杂合的 T305/306AV 突变足以恢复正常的 LTP 和空间学习。在与 AS 相比，DS 中 CaMKII 的过度磷酸化也可以被靶向药理学上（如果我们假设的潜在机制是正确的）。因此，该项目将不仅可以进一步深入了解正常突触的机制 DS 中的功能及其损伤，而且还具有直接打开恢复 DS 患者认知功能的新治疗途径。