Investigating the role of CDKL5 in the synapse

项目摘要 编码细胞周期蛋白依赖性激酶样5（CDKL 5）的X连锁基因突变导致儿童癫痫 被称为CDKL 5疾病的脑病。这种疾病的特点是一系列异质性的临床表现， 症状包括早发性癫痫发作、明显的张力减退、自闭症样特征和严重的 神经发育障碍为了证实CDKL5紊乱的遗传因果关系，我们生成了第一个 Cdkl5敲除（KO）小鼠，发现缺乏CDKL5的小鼠反映了CDKL5的几个标志性症状。 人类疾病，包括自闭症样行为、运动控制受损、神经诱发事件中断， 相关电位，学习和记忆力差。有趣的是，Cdkl5 KO小鼠也表现出受干扰的树突状细胞， 棘密度、形态和LTP。这些早期发现表明CDKL5在神经元凋亡中的重要作用。 突触功能然而，CDKL 5在这方面的具体作用，特别是开发后的作用，仍然存在。 未知考虑到这些由CDKL 5缺失引起的突触表型，以及我最近使用一种 一种新的CDKL5成人KO模型，我假设CDKL5表达在成年期是维持CDKL5表达所必需的。 适当的突触稳态、电路通信和行为输出。因此，本提案的目的是 为了阐明CDKL 5在突触功能中的成年需求，通过1）确定以下的充分性： CDKL 5在恢复成年期功能丧失的回路和行为缺陷中的作用，以及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 关于疾病可逆性的基本临床前信息，并为未来的发展铺平道路 为CDKL5疾病患者提供更有针对性的治疗。

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.