Restoring synaptic function in Down Syndrome mice

项目摘要 唐氏综合征(DS)模型小鼠有三种突触功能异常， 解释DS的认知缺陷：长时程增强(LTP)降低和长时程增强 谷氨酸能突触的时程抑制(LTD)以及增强的抑制性传递 在GABA能突触。我们最近发表的研究表明，这三个观察到的突触 功能障碍应由钙/钙调蛋白依赖性的过度磷酸化引起 蛋白激酶II(CaMKII)在DS小鼠中可见。我们最近未发表的研究表明 引起DS小鼠CaMKII过度磷酸化的可能机制。 重要的是，这种机制也可以通过药物干预而成为靶点。 作为原则证明，本项目将侧重于总体问题的两个方面： (目标1)测试DS小鼠CaMKII过度磷酸化的根本原因(使用 新的突变小鼠品系已经在实验室中产生，并且不能用于 拟议的基本机制)； (目的2)通过T305/306过度磷酸化的遗传逆转恢复正常的LTP DS小鼠(使用目前实验室可获得的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，恢复 认知行为任务，以及恢复也通过药理学手段。 值得注意的是，尽管提出逆转认知障碍的建议可能看起来很荒谬 非常复杂的综合症通过相当简单的干预，实际上是有先例的 成功：在一个导致认知障碍的不同遗传条件的模型中， Angelman综合征(AS)，CaMKII也是高度磷酸化的，甚至是杂合子 T305/306AV突变足以恢复正常的LTP和空间学习。在……里面 与AS相比，DS中CaMKII的过度磷酸化也可以作为靶点 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 不仅对正常突触背后的机制提供了重要的进一步洞察 功能及其损害，但也有巨大的潜力，直接打开一个 恢复DS患者认知功能的新治疗途径。

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 Our recent unpublished work indicates an intriguing possible mechanism for the cause of CaMKII hyper-phosphorylation in the DS mice.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