Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA.
Department of Neuroscience, Neurology, and Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA.
Nat Commun. 2019 Jun 14;10(1):2655. doi: 10.1038/s41467-019-10689-w.
CDKL5 deficiency disorder (CDD) is characterized by epilepsy, intellectual disability, and autistic features, and CDKL5-deficient mice exhibit a constellation of behavioral phenotypes reminiscent of the human disorder. We previously found that CDKL5 dysfunction in forebrain glutamatergic neurons results in deficits in learning and memory. However, the pathogenic origin of the autistic features of CDD remains unknown. Here, we find that selective loss of CDKL5 in GABAergic neurons leads to autistic-like phenotypes in mice accompanied by excessive glutamatergic transmission, hyperexcitability, and increased levels of postsynaptic NMDA receptors. Acute, low-dose inhibition of NMDAR signaling ameliorates autistic-like behaviors in GABAergic knockout mice, as well as a novel mouse model bearing a CDD-associated nonsense mutation, CDKL5 R59X, implicating the translational potential of this mechanism. Together, our findings suggest that enhanced NMDAR signaling and circuit hyperexcitability underlie autistic-like features in mouse models of CDD and provide a new therapeutic avenue to treat CDD-related symptoms.
CDKL5 缺乏症（CDD）的特征是癫痫、智力障碍和自闭症特征，CDKL5 缺乏的小鼠表现出一系列类似于人类疾病的行为表型。我们之前发现，前脑谷氨酸能神经元中的 CDKL5 功能障碍导致学习和记忆缺陷。然而，CDD 自闭症特征的发病机制仍不清楚。在这里，我们发现 GABA 能神经元中选择性缺失 CDKL5 会导致小鼠出现类似自闭症的表型，伴有过度的谷氨酸能传递、过度兴奋和突触后 NMDA 受体水平升高。急性、低剂量抑制 NMDA 受体信号可改善 GABA 能敲除小鼠的自闭症样行为，以及一种新型携带 CDD 相关无义突变的小鼠模型 CDKL5 R59X，表明该机制具有转化潜力。总之，我们的研究结果表明，增强的 NMDA 受体信号和电路过度兴奋是 CDD 小鼠模型中自闭症样特征的基础，并为治疗 CDD 相关症状提供了新的治疗途径。
