Neuron-Type Specific Loss of CDKL5 Leads to Alterations in mTOR Signaling and Synaptic Markers
| Autor: | Jyothi Arikkath, Ethan J. Schroeder, Eunju Seong, Cheryl Ligon, Li Yuan, C B Gurumurthy, Nicholas W. DeKorver |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cell signaling Neuroscience (miscellaneous) Striatum Biology Protein Serine-Threonine Kinases Inhibitory postsynaptic potential Hippocampus Models Biological Article 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine Animals GABAergic Neurons Mechanistic target of rapamycin PI3K/AKT/mTOR pathway Mice Knockout Neurons TOR Serine-Threonine Kinases Reproducibility of Results Neural Inhibition Rats Mice Inbred C57BL 030104 developmental biology Neurology nervous system Organ Specificity Synapses Excitatory postsynaptic potential biology.protein GABAergic Signal transduction Neuroscience 030217 neurology & neurosurgery Biomarkers Signal Transduction |
| Zdroj: | Mol Neurobiol |
| ISSN: | 1559-1182 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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