Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
Developmental Neuroscience, Munroe-Meyer Institute, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
Mol Neurobiol. 2019 Jun;56(6):4151-4162. doi: 10.1007/s12035-018-1346-8. Epub 2018 Oct 4.
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.
CDKL5 障碍是一种与癫痫、发育迟缓、自闭症和相关表型相关的毁灭性神经发育障碍。该障碍中已鉴定出编码 CDKL5 的 CDKL5 基因突变。CDKL5 是一种与丝氨酸-苏氨酸激酶具有同源性且功能不完全明确的蛋白质。我们生成并验证了一种携带 CDKL5 基因 floxed 等位基因和多克隆抗 CDKL5 抗体的小鼠模型。CDKL5 在皮质、海马体和纹状体中表达良好，定位于突触小体和细胞核，并在海马体中具有发育调节作用。使用 Cre 介导的机制，我们从兴奋性 CaMKIIα 阳性神经元或抑制性 GABA 能神经元中删除 CDKL5。我们的数据表明，皮质兴奋性神经元或纹状体抑制性神经元中 CDKL5 的缺失以不同的方式改变了机械靶标雷帕霉素 (mTOR) 信号通路的一些成分的表达。进一步在皮质兴奋性神经元或纹状体抑制性神经元中缺失 CDKL5 会以神经元类型特异性的方式导致突触标记物水平发生改变。总之，这些数据支持这样一种模型，即 CDKL5 的缺失以神经元类型特异性的方式改变 mTOR 信号和突触组成，并表明 CDKL5 可能在兴奋性和抑制性神经元的细胞信号中具有不同的功能作用。因此，这些研究为 CDKL5 的生物学提供了新的见解，并表明 CDKL5 障碍中的分子病理学可能具有不同的神经元类型特异性起源和影响。
