Altered NMDAR signaling underlies autistic-like features in mouse models of CDKL5 deficiency disorder

Sheng Tang, Barbara Terzic, I-Ting Judy Wang, Nicolas Sarmiento, Katherine Sizov, Yue Cui, Hajime Takano, Eric D. Marsh, Zhaolan Zhou () and Douglas A. Coulter ()
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Sheng Tang: University of Pennsylvania Perelman School of Medicine
Barbara Terzic: University of Pennsylvania Perelman School of Medicine
I-Ting Judy Wang: University of Pennsylvania Perelman School of Medicine
Nicolas Sarmiento: University of Pennsylvania Perelman School of Medicine
Katherine Sizov: University of Pennsylvania Perelman School of Medicine
Yue Cui: University of Pennsylvania Perelman School of Medicine
Hajime Takano: University of Pennsylvania Perelman School of Medicine
Eric D. Marsh: University of Pennsylvania Perelman School of Medicine
Zhaolan Zhou: University of Pennsylvania Perelman School of Medicine
Douglas A. Coulter: University of Pennsylvania Perelman School of Medicine

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-10689-w

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