Loss of CDKL5 disrupts kinome profile and event-related potentials leading to autistic-like phenotypes in mice.

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Universal Screening for Autism in Toddlers

TitleLoss of CDKL5 disrupts kinome profile and event-related potentials leading to autistic-like phenotypes in mice.
Publication TypeJournal Article
Year of Publication2012
AuthorsWang, I-TJudy, Allen, M, Goffin, D, Zhu, X, Fairless, AH, Brodkin, ES, Siegel, SJ, Marsh, ED, Blendy, JA, Zhou, Z
JournalProc Natl Acad Sci U S A
Volume109
Issue52
Pagination21516-21
Date Published2012 Dec 26
ISSN1091-6490
KeywordsAnimals, Anxiety, Autistic Disorder, Behavior, Animal, Electroencephalography, Evoked Potentials, Hyperkinesis, Memory, Mice, Mice, Inbred C57BL, Mice, Knockout, Neurons, Phenotype, Protein-Serine-Threonine Kinases, Proteome, Proto-Oncogene Proteins c-akt, Seizures, Signal Transduction, Social Behavior, TOR Serine-Threonine Kinases
Abstract

Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene have been identified in neurodevelopmental disorders including atypical Rett syndrome (RTT), autism spectrum disorders (ASDs), and early infantile epileptic encephalopathy. The biological function of CDKL5 and its role in the etiology of these disorders, however, remain unclear. Here we report the development of a unique knockout mouse model of CDKL5-related disorders and demonstrate that mice lacking CDKL5 show autistic-like deficits in social interaction, as well as impairments in motor control and fear memory. Neurophysiological recordings reveal alterations in event-related potentials (ERPs) similar to those observed in RTT and ASDs. Moreover, kinome profiling uncovers disruption of multiple signal transduction pathways, including the AKT-mammalian target of rapamycin (mTOR) cascade, upon Cdkl5 loss-of-function. These data demonstrate that CDKL5 regulates signal transduction pathways and mediates autistic-like phenotypes and together establish a causal role for Cdkl5 loss-of-function in neurodevelopmental disorders.

DOI10.1073/pnas.1216988110
Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID23236174
PubMed Central IDPMC3535652
Grant ListMH080718 / MH / NIMH NIH HHS / United States
R00 NS058391 / NS / NINDS NIH HHS / United States
K02 NS065975 / NS / NINDS NIH HHS / United States
T32 GM008076 / GM / NIGMS NIH HHS / United States
R01 MH080718 / MH / NIMH NIH HHS / United States
P30 HD018655 / HD / NICHD NIH HHS / United States
T32 MH017168 / MH / NIMH NIH HHS / United States
K99 NS058391 / NS / NINDS NIH HHS / United States
NS058391 / NS / NINDS NIH HHS / United States
P30 HD18655 / HD / NICHD NIH HHS / United States
MH017168 / MH / NIMH NIH HHS / United States
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