Altered NMDAR signaling underlies autistic-like features in mouse models of CDKL5 deficiency disorder.
Nat Commun
; 10(1): 2655, 2019 06 14.
Article
em En
| MEDLINE
| ID: mdl-31201320
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Espasmos Infantis
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Transdução de Sinais
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Proteínas Serina-Treonina Quinases
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Receptores de N-Metil-D-Aspartato
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Neurônios GABAérgicos
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Síndromes Epilépticas
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Female
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Humans
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Male
Idioma:
En
Revista:
Nat Commun
Ano de publicação:
2019
Tipo de documento:
Article