Journal Article

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

Tang, Sheng, Marsh, Eric D., Sizov, Katherine, Wang, I-Ting Judy, Takano, Hajime, Zhou, Zhaolan, Coulter, Douglas A., Terzic, Barbara, Sarmiento, Nicolas, Cui, Yue

2019

Overview

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. Mouse models of CDKL5 deficiency disorder (CDD) recapitulate multiple clinical symptoms of CDD, such as intellectual disability and autism. Here, the authors show that selective loss of CDKL5 from GABAergic neurons leads to social deficits and stereotypic behaviors, which can be ameliorated through inhibition of NMDAR signaling.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 631/136 / 631/378 / 64/60 / 9/74 / Animal models / Animals / Autism / Behavior, Animal - drug effects / Codon, Nonsense / Constellations / Deficiency diseases / Disease Models, Animal / Epilepsy / Epileptic Syndromes - drug therapy / Epileptic Syndromes - genetics / Epileptic Syndromes - pathology / Excitatory Amino Acid Antagonists - pharmacology / Excitatory Amino Acid Antagonists - therapeutic use / Female / Forebrain / GABAergic Neurons - pathology / Glutamatergic transmission / Glutamic acid receptors (ionotropic) / Human behavior / Humanities and Social Sciences / Humans / Immunological memory / Male / Memantine - pharmacology / Memantine - therapeutic use / Mice / Mice, Inbred C57BL / Mice, Knockout / multidisciplinary / Mutation / N-Methyl-D-aspartic acid receptors / Neurons / Nonsense mutation / Phenotypes / Prosencephalon - cytology / Prosencephalon - drug effects / Prosencephalon - pathology / Protein-Serine-Threonine Kinases - deficiency / Protein-Serine-Threonine Kinases - genetics / Receptors / Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors / Receptors, N-Methyl-D-Aspartate - metabolism / Rodents / Science / Science (multidisciplinary) / Signal Transduction - genetics / Signaling / Signs and symptoms / Spasms, Infantile - drug therapy / Spasms, Infantile - genetics / Spasms, Infantile - pathology / Treatment Outcome