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Nat Commun. 2019 Jun 14;10(1):2655. doi: 10.1038/s41467-019-10689-w.

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

Author information

1
Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA.
2
Department of Neuroscience, Neurology, and Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA.
3
The Research Institute of the Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.
4
Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA. zhaolan@pennmedicine.upenn.edu.
5
Department of Neuroscience, Neurology, and Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA. coulterd@email.chop.edu.
6
The Research Institute of the Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA. coulterd@email.chop.edu.

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.

PMID:
31201320
PMCID:
PMC6572855
DOI:
10.1038/s41467-019-10689-w
[Indexed for MEDLINE]
Free PMC Article

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