Neuron-Type Specific Loss of CDKL5 Leads to Alterations in mTOR Signaling and Synaptic Markers

Ethan Schroeder, Li Yuan, Eunju Seong, Cheryl Ligon, Nicholas DeKorver, C. B. Gurumurthy, Jyothi Arikkath

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

CDKL5 disorder is a devastating neurodevelopmental disorder associated with epilepsy, developmental retardation, autism, and related phenotypes. Mutations in the CDKL5 gene, encoding CDKL5, have been identified in this disorder. CDKL5 is a protein with homology to the serine-threonine kinases and incompletely characterized function. We generated and validated a murine model bearing a floxed allele of CDKL5 and polyclonal antibodies to CDKL5. CDKL5 is well expressed in the cortex, hippocampus, and striatum, localized to synaptosomes and nuclei and developmentally regulated in the hippocampus. Using Cre-mediated mechanisms, we deleted CDKL5 from excitatory CaMKIIα-positive neurons or inhibitory GABAergic neurons. Our data indicate that loss of CDKL5 in excitatory neurons of the cortex or inhibitory neurons of the striatum differentially alters expression of some components of the mechanistic target of rapamycin (mTOR) signaling pathway. Further loss of CDKL5 in excitatory neurons of the cortex or inhibitory neurons of the striatum leads to alterations in levels of synaptic markers in a neuron-type specific manner. Taken together, these data support a model in which loss of CDKL5 alters mTOR signaling and synaptic compositions in a neuron-type specific manner and suggest that CDKL5 may have distinct functional roles related to cellular signaling in excitatory and inhibitory neurons. Thus, these studies provide new insights into the biology of CDKL5 and suggest that the molecular pathology in CDKL5 disorder may have distinct neuron-type specific origins and effects.

Original languageEnglish (US)
Pages (from-to)4151-4162
Number of pages12
JournalMolecular Neurobiology
Volume56
Issue number6
DOIs
StatePublished - Jun 1 2019

Keywords

  • CDKL5
  • CDKL5 disorder
  • Signaling
  • Synaptic
  • mTOR

ASJC Scopus subject areas

  • Neurology
  • Cellular and Molecular Neuroscience

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