Investigating the role of CDKL5 in the synapse

研究 CDKL5 在突触中的作用

• 批准号: 9469699
• 负责人: Barbara Terzic
• 金额: $ 4.4万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-19 至 2019-09-18
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9469699
• 关键词: Address; Adult; Affect; Age; Auditory; Autistic Disorder; Behavior; Behavioral; Cell Culture Techniques; Childhood; Clinical; Communication; Cyclin-Dependent Kinases; Data; Dendritic Spines; Development; Developmental Process; Diagnosis; Disease; Epilepsy; Etiology; Event; Event-Related Potentials; Exhibits; Exons; Foundations; Future; Gene Expression; Genes; Genetic; Genetic Recombination; Goals; Hippocampus (Brain); Homeostasis; Knock-out; Knockout Mice; Learning; Ligands; Link; Maintenance; Mediating; Memory; Mind; Modeling; Molecular; Morphology; Mus; Muscle hypotonia; Mutation; Nervous system structure; Neurodevelopmental Impairment; Neurons; Neurophysiology - biologic function; Output; Pathogenesis; Pathway interactions; Patients; Phenotype; Phosphorylation; Phosphotransferases; Prosencephalon; Proteins; Regulation; Role; Seizures; Symptoms; Synapses; Synaptic plasticity; System; Tamoxifen; Testing; Therapeutic; Wild Type Mouse; Work; density; early onset; epileptic encephalopathies; excitatory neuron; hippocampal pyramidal neuron; human disease; in vivo; insight; knock-down; loss of function; motor control; motor impairment; netrin-G1; novel; patient population; postnatal; pre-clinical; restoration; synaptic function; targeted treatment; therapeutic development; ubiquitin-protein ligase

PROJECT SUMMARY Mutations in the X-linked gene encoding cyclin-dependent kinase-like 5 (CDKL5) cause the childhood epileptic encephalopathy known as CDKL5 disorder. The disease is characterized by a heterogeneous array of clinical symptoms including early-onset seizures, marked hypotonia, autistic-like features, and severe neurodevelopmental impairment. To confirm the genetic causality of CDKL5 disorder, we generated the first Cdkl5 knockout (KO) mouse and found that mice lacking CDKL5 mirror several hallmark symptoms of the human disease, including autistic-like behaviors, impaired motor control, disrupted auditory-evoked event- related potentials, and poor learning and memory. Interestingly, Cdkl5 KO mice also exhibit perturbed dendritic spine density, morphology, and LTP. These early findings suggest an important role for CDKL5 in neuronal synapse function. However, CDKL5’s specific role in this context, particularly post-development, remains unknown. Given these synaptic phenotypes caused by CDKL5 loss, and my recent preliminary data using a novel adult KO model of CDKL5, I hypothesize that CDKL5 expression is required in adulthood to maintain proper synaptic homeostasis, circuit communication, and behavioral output. Thus, the goal of this proposal is to elucidate the adulthood requirement of CDKL5 in synaptic function by 1) determining the sufficiency of CDKL5 in restoring loss-of-function circuit and behavioral deficits at adulthood and 2) determining the extent to which CDKL5 modulates synaptic density and morphology in vivo. My ultimate goal is to determine a novel role for CDKL5 in the maintenance of adult neural function. These studies will provide essential preclinical information regarding disease reversibility, and pave the way for the future development of more targeted therapeutics for CDKL5 disorder patients.

项目摘要 编码细胞周期蛋白依赖性激酶5（CDKL5）的X连锁基因中的突变导致儿童癫痫病 脑病称为CDKL5疾病。该疾病的特征是一系列临床阵列 症状包括早发作，明显的肌张力，类似加速的特征和严重的症状 神经发育障碍。为了确认CDKL5疾病的遗传因果关系，我们产生了第一个 CDKL5敲除（KO）鼠标，发现缺少CDKL5的老鼠镜面了几个标志的符号 人类疾病，包括侵略性行为，运动控制受损，听觉引起的事件破坏 - 相关潜力，学习和记忆力不佳。有趣的是，CDKL5 KO小鼠还表现出扰动的树突状 脊柱密度，形态和LTP。这些早期发现表明CDKL5在神经元中的重要作用 突触功能。但是，在这种情况下，CDKL5的具体作用，尤其是在开发后，仍然是 未知。考虑到由CDKL5损失引起的这些合成表型，以及我最近的初步数据使用 新型的成人KO CDKL5模型，我假设成年后需要CDKL5表达 适当的突触体内稳态，电路通信和行为输出。那是该提议的目标是 通过1）确定足够的能力 CDKL5在恢复功能丧失电路和行为方面定义在成年时，2）确定 CDKL5在体内调节突触密度和形态的程度。我的最终目标是 确定CDKL5在维持成人神经功能中的新作用。这些研究将提供 有关疾病可逆性的基本临床前信息，并为未来发展铺平了道路 针对CDKL5疾病患者的更多靶向疗法。