學術產出-Periodical Articles

Article View/Open

Publication Export

Google ScholarTM

政大圖書館

Citation Infomation

題名 Dopaminergic loss of cyclin-dependent kinase-like 5 recapitulates methylphenidate-remediable hyperlocomotion in mouse model of CDKL5 deficiency disorder
作者 廖文霖
Liao, Wenlin
Jhang, Cian-Ling
Lee, Hom-Yi
Chen,  Jin-Chung
貢獻者 神科所
關鍵詞 dopamine ; attention-deficit/hyperactivity disorder ; corpus striatum ; cyclins ; methylphenidate ; neostriatum ; phosphorylation ; phosphotransferases ; mice ; dopaminergic neurons
日期 2020-06
上傳時間 13-Nov-2020 15:40:42 (UTC+8)
摘要 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.
關聯 Human Molecular Genetics, Vol.29, No.14, pp.2408-2419
資料類型 article
DOI https://doi.org/10.1093/hmg/ddaa122
dc.contributor 神科所
dc.creator (作者) 廖文霖
dc.creator (作者) Liao, Wenlin
dc.creator (作者) Jhang, Cian-Ling
dc.creator (作者) Lee, Hom-Yi
dc.creator (作者) Chen,  Jin-Chung
dc.date (日期) 2020-06
dc.date.accessioned 13-Nov-2020 15:40:42 (UTC+8)-
dc.date.available 13-Nov-2020 15:40:42 (UTC+8)-
dc.date.issued (上傳時間) 13-Nov-2020 15:40:42 (UTC+8)-
dc.identifier.uri (URI) http://nccur.lib.nccu.edu.tw/handle/140.119/132553-
dc.description.abstract (摘要) 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.
dc.format.extent 152 bytes-
dc.format.mimetype text/html-
dc.relation (關聯) Human Molecular Genetics, Vol.29, No.14, pp.2408-2419
dc.subject (關鍵詞) dopamine ; attention-deficit/hyperactivity disorder ; corpus striatum ; cyclins ; methylphenidate ; neostriatum ; phosphorylation ; phosphotransferases ; mice ; dopaminergic neurons
dc.title (題名) Dopaminergic loss of cyclin-dependent kinase-like 5 recapitulates methylphenidate-remediable hyperlocomotion in mouse model of CDKL5 deficiency disorder
dc.type (資料類型) article
dc.identifier.doi (DOI) 10.1093/hmg/ddaa122
dc.doi.uri (DOI) https://doi.org/10.1093/hmg/ddaa122