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.
Highlights
Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene cause early-onset epileptic encephalopathy [1]
A constitutive knockout allele of Cdkl5 was produced by germline deletion of exon 4 of a Cdkl5 conditional knockout allele produced by standard gene targeting in embryonic stem cells (Figure S1A)
Signaling deficits in Cdkl5 knockout mice we examined whether expression of Mecp2 protein and signaling factors known to be altered in Mecp2 knockout mice might be affected in Cdkl5 knockouts
Summary
Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene cause early-onset epileptic encephalopathy [1]. CDKL5 disorder shares several features with Rett Syndrome, a neurodevelopmental disorder caused by mutations in the X-linked MECP2 gene [2], recent work assessing data from 86 subjects has argued that it should be considered a distinct clinical entity, primarily due to its early onset and lack of clinical regression following a period of normal development [3]. The disorder is most frequently associated with nonsense or putative detrimental missense mutations and is thought to be caused by a loss of CDKL5 function, no clear relationship between the type or location of mutations and symptom severity has been reported [6]. Data demonstrate that CDKL5 can bind to and phosphorylate MECP2 in vitro, suggesting a possible molecular link between CDKL5 disorder and Rett Syndrome [8]
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