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    Title: Dopaminergic loss of cyclin-dependent kinase-like 5 recapitulates methylphenidate-remediable hyperlocomotion in mouse model of CDKL5 deficiency disorder
    Authors: 廖文霖
    Liao, Wenlin
    Jhang, Cian-Ling
    Lee, Hom-Yi
    Chen,  Jin-Chung
    Contributors: 神科所
    Keywords: dopamine;attention-deficit/hyperactivity disorder;corpus striatum;cyclins;methylphenidate;neostriatum;phosphorylation;phosphotransferases;mice;dopaminergic neurons
    Date: 2020-06
    Issue Date: 2020-11-13 15:40:42 (UTC+8)
    Abstract: Cyclin-dependent kinase-like 5 (CDKL5), a serine-threonine kinase encoded by an X-linked gene, is highly expressed in the mammalian forebrain. Mutations in this gene cause CDKL5 deficiency disorder, a neurodevelopmental encephalopathy characterized by early-onset seizures, motor dysfunction, and intellectual disability. We previously found that mice lacking CDKL5 exhibit hyperlocomotion and increased impulsivity, resembling the core symptoms in attention-deficit hyperactivity disorder (ADHD). Here, we report the potential neural mechanisms and treatment for hyperlocomotion induced by CDKL5 deficiency. Our results showed that loss of CDKL5 decreases the proportion of phosphorylated dopamine transporter (DAT) in the rostral striatum, leading to increased levels of extracellular dopamine and hyperlocomotion. Administration of methylphenidate (MPH), a DAT inhibitor clinically effective to improve symptoms in ADHD, significantly alleviated the hyperlocomotion phenotype in Cdkl5 null mice. In addition, the improved behavioral effects of MPH were accompanied by a region-specific restoration of phosphorylated dopamine- and cAMP-regulated phosphoprotein Mr 32 kDa, a key signaling protein for striatal motor output. Finally, mice carrying a Cdkl5 deletion selectively in DAT-expressing dopaminergic neurons, but not dopamine receptive neurons, recapitulated the hyperlocomotion phenotype found in Cdkl5 null mice. Our findings suggest that CDKL5 is essential to control locomotor behavior by regulating region-specific dopamine content and phosphorylation of dopamine signaling proteins in the striatum. The direct, as well as indirect, target proteins regulated by CDKL5 may play a key role in movement control and the therapeutic development for hyperactivity disorders.
    Relation: Human Molecular Genetics, Vol.29, No.14, pp.2408-2419
    Data Type: article
    DOI link: https://doi.org/10.1093/hmg/ddaa122
    DOI: 10.1093/hmg/ddaa122
    Appears in Collections:[Graduate Institute of Neuroscience] Periodical Articles

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