Cerebellar alterations in a model of Down syndrome: The role of the Dyrk1A gene

NEUROBIOLOGY OF DISEASE

卷:110

Article

Garcia-Cerro, Susana^1,6  Vidal, Veronica¹  Lantigua, Sara¹  Teresa Berciano, Maria^2,3  Lafarga, Miguel^2,3  Ramos-Cabrer, Pedro^4,5  Padro, Daniel⁴  Rueda, Noemi¹  Martinez-Cue, Carmen¹ 

[1] Univ Cantabria, Fac Med, Dept Physiol & Pharmacol, Santander 39011, Spain

[2] Univ Cantabria, IDIVAL, Dept Anat & Cell Biol, Santander 39011, Spain

[3] Univ Cantabria, IDIVAL, CIBERNED, Santander 39011, Spain

[4] CIC BiomaGUNE, Mol Imaging Unit, Donostia San Sebastian 20009, Spain

[5] Ikerbasque, Bilbao 48013, Spain

[6] Univ Barcelona, Fac Med, Pharmacol Unit, Dept Clin Fdn, Barcelona 08036, Spain

关键词: Down syndrome;    Cerebellum;    Ts65Dn;    Dyrk1A;   

DOI  :  10.1016/j.nbd.2017.12.002

来源: Elsevier

【 摘 要 】

Down syndrome (DS) is characterized by a marked reduction in the size of the brain and cerebellum. These changes play an important role in the motor alterations and cognitive disabilities observed in this condition. The Ts65Dn (TS) mouse, the most commonly used model of DS, reflects many DS phenotypes, including alterations in cerebellar morphology. One of the genes that is overexpressed in both individuals with DS and TS mice is DYRK1A/DyrklA (dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A), which has been implicated in the altered cerebellar structural and functional phenotypes observed in both populations. The aim of this study was to evaluate the effect of DyrklA on different alterations observed in the cerebellum of TS animals. TS mice were crossed with Dyrk1A + / - KO mice to obtain mice with a triplicate segment of Mmu16 that included DyrklA (TS + / + / +), mice with triplicate copies of the same genes that carried only two copies of DyrklA (TS + / + / -), euploid mice that expressed a normal dose of DyrklA (CO + / +) and CO animals with a single copy of DyrklA (CO + / -). Male mice were used for all experiments. The normalization of the DyrklA gene dosage did not rescue the reduced cerebellar volume. However, it increased the size of the granular and molecular layers, the densities of granular and Purkinje cells, and dendritic arborization. Furthermore, it improved the excitatory/inhibitory balance and walking pattern of TS +/ + / - mice. These results support the hypothesis that DyrklA is involved in some of the structural and functional cerebellar phenotypes observed in the TS mouse model.

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