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）的特征在于癫痫，智力残疾和自闭症特征，而CDKL5缺乏症小鼠表现出令人联想到人类疾病的行为表型。我们先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障碍。但是，CDD自闭症特征的致病原因仍然未知。在这里，我们发现在GABA能神经元中CDKL5的选择性丧失导致小鼠出现自闭症样表型，并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NMDAR信号可改善GABA能基因敲除小鼠以及带有CDD相关无义突变CDKL5 R59X的新型小鼠模型的自闭症行为，暗示这种机制的翻译潜力。在一起，我们的发现表明，增强的NMDAR信号传导和电路过度兴奋性是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。