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CaMKII hypo-nitrosylatlon In age-related decline of synaptic plasticity and cognition

CaMKII 低亚硝基化在与年龄相关的突触可塑性和认知能力下降中

基本信息

批准号：
10436149
负责人：
Nicole Rumian
金额：
$ 3.64万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-05 至 2023-03-04
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10436149
关键词：
Affect Age-associated memory impairment Aging Animals Anxiety Behavior Behavioral Behavioral Assay Binding Biochemical Cognition Cysteine Data Dependence Development Elderly Electrophysiology (science)Excitatory Synapse Exploratory Behavior Frequencies Hippocampus (Brain)Image Impaired cognition Impairment Intrabody Investigation Knock-in Mouse L-Type Calcium Channels Lead Learning Long-Term Potentiation Mediating Memory Modeling Molecular Monitor Motor Activity Movement Mus Mutant Strains Mice Mutation N-Methyl-D-Aspartate Receptors Neurons Output Pharmacology Play Population Problem Solving Protein Overexpression Proteins Quality of life Radial Regulation Role Short-Term Memory Synapses Synaptic Potentials Synaptic plasticity Techniques Testing Therapeutic Therapeutic Intervention Wild Type Mouse age related aged arm base calmodulin-dependent protein kinase II cognitive function experimental study insight mutant spatial memory water maze young adult

项目摘要

PROJECT SUMMARY Synaptic plasticity, specifically long-term potentiation (LTP), is thought to underlie learning, memory, and cognition. This function is disrupted in aging populations, where cognitive decline, such as forgetfulness and decreased problem-solving capacity, is a well known impairment. LTP requires Ca2+/calmodulin (CaM)- dependent protein kinase II (CaMKII), its Ca2+-independent autonomous activity and regulated binding to N- methyl-D-aspartate receptor (NMDAR), which results in CaMKII translocation to excitatory synapses. It has recently been suggested that hypo-nitrosylation may underlie the cognitive impairment seen in aging. My preliminary live-imaging data demonstrate that application of an NO donor is sufficient to stimulate CaMKII translocation to excitatory synapses and that this effect is abolished in a genetically modified knock-in mouse line, CaMKIIΔSNO, in which CaMKII is rendered un-nitrosylable. Other preliminary data from the lab suggests that these mice demonstrate normal high frequency stimulation (HFS)-induced LTP, but have impaired theta burst stimulation (TBS)-induced LTP, which mimics what is seen in aged animals. My proposal will test the hypotheses that (i) CaMKII synaptic targeting can be regulated by nitrosylation and (ii) CaMKII hypo-nitrosylation mediates both age-related LTP and cognitive impairment. Specifically, I will use live-imaging, biochemical, electrophysiological, and behavioral techniques on wild-type and mutant mice to determine the effect of CaMKII nitrosylation on synaptic plasticity and determine if hypo-nitrosylation underlies cognitive impairment seen in aging. Notably, this project utilizes intrabodies, which allow for simultaneous imaging of multiple endogenous proteins without the normal confounds seen in protein overexpression experiments, to live-monitor endogenous CaMKII targeting and an unpublished mouse line, CaMKIIΔSNO. Further, this project will provide a comprehensive investigation of the role of CaMKII nitrosylation in synaptic plasticity and aging, as it begins at the molecular level and proceeds through to functional behavioral outputs. The results from this project will not only elucidate the cellular and molecular role of CaMKII nitrosylation in synaptic plasticity, but also provide insights into how hypo- nitrosylation may underlie the cognitive impairment seen in aging, thus leading to a better understanding of synaptic plasticity and potential therapeutic interventions for aging populations.

项目总结突触的可塑性，特别是长时程增强(LTP)，被认为是学习、记忆和认知力。这一功能在老龄化人群中被破坏，认知能力下降，如健忘和解决问题的能力下降，是一种众所周知的障碍。LTP需要钙/钙调素(CaM)- 依赖蛋白激酶II(CaMKII)及其钙非依赖性自主活性和与N-的调节结合甲基-D-天冬氨酸受体(NMDAR)，导致CaMKII易位到兴奋性突触。它有最近有人提出，次亚硝化可能是衰老过程中认知障碍的基础。我的初步的活体成像数据表明，应用NO供体足以刺激CaMKII 易位到兴奋性突触，这一效应在转基因敲入小鼠中被取消 CaMKIIΔSNO行，其中CaMKII变为不可亚硝化。实验室的其他初步数据表明，这些小鼠表现出正常的高频刺激(HFS)诱导的LTP，但已经损害了theta Burst 刺激(TBS)诱导的LTP，模仿在老年动物中看到的。我的提议将检验这些假说 (I)CaMKII突触靶向可受亚硝化调节，(Ii)CaMKII次亚硝基化介导与年龄相关的长时程增强和认知障碍。具体地说，我将使用现场成像，生化，用电生理和行为学技术研究CaMKII对野生型和突变小鼠的影响亚硝酸化对突触可塑性的影响并确定次亚硝酸化是否导致认知障碍衰老。值得注意的是，该项目利用体内，允许同时成像多个内源性没有蛋白质过表达实验中正常混杂的蛋白质，以实时监测内源性 CaMKII靶向和一个未发表的小鼠品系CaMKIIΔSNO。此外，该项目将提供一个全面的从分子水平研究CaMKII亚硝化在突触可塑性和衰老中的作用并继续进行到功能行为输出。这个项目的结果不仅将阐明 CaMKII亚硝化在突触可塑性中的细胞和分子作用，但也提供了对如何下调突触可塑性的见解。亚硝酸化可能是衰老中认知障碍的基础，从而导致更好地理解突触可塑性和对老龄化人口的潜在治疗干预。