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


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.

Pubmed ID: 23236174


  • Wang IT
  • Allen M
  • Goffin D
  • Zhu X
  • Fairless AH
  • Brodkin ES
  • Siegel SJ
  • Marsh ED
  • Blendy JA
  • Zhou Z


Proceedings of the National Academy of Sciences of the United States of America

Publication Data

December 26, 2012

Associated Grants

  • Agency: NINDS NIH HHS, Id: K02 NS065975
  • Agency: NIMH NIH HHS, Id: MH017168
  • Agency: NIMH NIH HHS, Id: MH080718
  • Agency: NINDS NIH HHS, Id: NS058391
  • Agency: NICHD NIH HHS, Id: P30 HD18655

Mesh Terms

  • Animals
  • 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