Department of Systems Pharmacology and Translational Therapeutics, and.
Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104.
J Neurosci. 2019 Jun 12;39(24):4814-4828. doi: 10.1523/JNEUROSCI.2041-18.2019. Epub 2019 Apr 5.
Pathogenic mutations in cyclin-dependent kinase-like 5 () result in CDKL5 deficiency disorder (CDD), a rare disease marked by early-life seizures, autistic behaviors, and intellectual disability. Although mouse models of CDD exhibit dendritic instability and alterations in synaptic scaffolding proteins, studies of glutamate receptor levels and function are limited. Here we used a novel mouse model of CDD, the knock-in mouse (R59X), to investigate changes in synaptic glutamate receptor subunits and functional consequences. Male mice were used for all experiments to avoid the confounding effects of X-inactivation that would be present in female heterozygous mice. We showed that adult male R59X mice recapitulated the behavioral outcomes observed in other mouse models of CDD, including social deficits and memory and learning impairments, and exhibited decreased latency to seizure upon pentylenetetrazol administration. Furthermore, we observed a specific increase in GluA2-lacking α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)-type glutamate receptors (AMPARs) in the adult R59X hippocampus, which is accompanied electrophysiologically by increased rectification ratio of AMPAR EPSCs and elevated early-phase long term potentiation (LTP). Finally, we showed that acute treatment with the GluA2-lacking AMPAR blocker IEM-1460 decreased AMPAR currents, and rescued social deficits, working memory impairments, and seizure behavior latency in R59X mice. CDKL5 deficiency disorder (CDD) is a rare disease marked by autistic-like behaviors, intellectual disability, and seizures. While synaptic dysfunction has been observed in mouse models of CDD, there is limited information on how synaptic alterations contribute to behavioral and functional changes in CDD. Here we reveal elevated hippocampal GluA2-lacking AMPAR expression in a novel mouse model of CDD that is accompanied by changes in synaptic AMPAR function and plasticity. We also show, for the first time, that acutely targeting GluA2-lacking AMPAR dysregulation rescues core synaptic and neurobehavioral deficits in CDD.
CDKL5 缺乏症（CDD）是一种罕见疾病，其特征为早发性癫痫、自闭症行为和智力障碍。尽管 CDD 的小鼠模型表现出树突不稳定和突触支架蛋白改变，但谷氨酸受体水平和功能的研究有限。在这里，我们使用一种新的 CDD 小鼠模型，即 R59X 敲入小鼠，研究突触谷氨酸受体亚基的变化及其功能后果。所有实验均使用雄性小鼠进行，以避免在雌性杂合子小鼠中存在的 X 染色体失活的混杂影响。我们表明，成年雄性 R59X 小鼠重现了其他 CDD 小鼠模型中观察到的行为结果，包括社交缺陷、记忆和学习障碍，并在戊四氮给药后表现出癫痫发作潜伏期缩短。此外，我们观察到成年 R59X 海马体中特定的 GluA2 缺失的 α-氨基-3-羟基-5-甲基-4-异恶唑丙酸型谷氨酸受体（AMPAR）增加，这在电生理上表现为 AMPAR EPSC 的整流比增加和早期长时程增强（LTP）升高。最后，我们表明，急性用 GluA2 缺失的 AMPAR 阻断剂 IEM-1460 处理可降低 AMPAR 电流，并挽救 R59X 小鼠的社交缺陷、工作记忆障碍和癫痫发作潜伏期。CDKL5 缺乏症（CDD）是一种罕见疾病，其特征为自闭症样行为、智力障碍和癫痫发作。尽管在 CDD 的小鼠模型中观察到突触功能障碍，但关于突触改变如何导致 CDD 中的行为和功能变化的信息有限。在这里，我们揭示了一种新型 CDD 小鼠模型中海马体中升高的 GluA2 缺失的 AMPAR 表达，其伴随着突触 AMPAR 功能和可塑性的改变。我们还首次表明，急性靶向 GluA2 缺失的 AMPAR 失调可挽救 CDD 的核心突触和神经行为缺陷。
