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PLoS One. 2014 May 16;9(5):e91613. doi: 10.1371/journal.pone.0091613. eCollection 2014.

Mapping pathological phenotypes in a mouse model of CDKL5 disorder.

Author information

1
Mouse Biology Unit, European Molecular Biology Laboratory (EMBL), Monterotondo, Italy.
2
Department of Neuroscience and National Institute of Neuroscience, University of Turin, Turin, Italy.
3
Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
4
Institute of Neuroscience, National Research Council (CNR), Pisa, Italy; Department of Neuroscience, Psychology, Drug Research and Child Health NEUROFARBA University of Florence, Florence, Italy.
5
Institute of Neuroscience, National Research Council (CNR), Pisa, Italy.
6
Institute of Neuroinformatics, University of Zürich and Swiss Federal Institute of Technology (ETH), Zurich, Switzerland.

Abstract

Mutations in cyclin-dependent kinase-like 5 (CDKL5) cause early-onset epileptic encephalopathy, a neurodevelopmental disorder with similarities to Rett Syndrome. Here we describe the physiological, molecular, and behavioral phenotyping of a Cdkl5 conditional knockout mouse model of CDKL5 disorder. Behavioral analysis of constitutive Cdkl5 knockout mice revealed key features of the human disorder, including limb clasping, hypoactivity, and abnormal eye tracking. Anatomical, physiological, and molecular analysis of the knockout uncovered potential pathological substrates of the disorder, including reduced dendritic arborization of cortical neurons, abnormal electroencephalograph (EEG) responses to convulsant treatment, decreased visual evoked responses (VEPs), and alterations in the Akt/rpS6 signaling pathway. Selective knockout of Cdkl5 in excitatory and inhibitory forebrain neurons allowed us to map the behavioral features of the disorder to separable cell-types. These findings identify physiological and molecular deficits in specific forebrain neuron populations as possible pathological substrates in CDKL5 disorder.

PMID:
24838000
PMCID:
PMC4023934
DOI:
10.1371/journal.pone.0091613
[Indexed for MEDLINE]
Free PMC Article

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