Regulation of the dopaminergic system in a murine model of aromatic L-amino acid decarboxylase deficiency

NEUROBIOLOGY OF DISEASE

卷:52

Article

Lee, Ni-Chung^1,2,3,4  Shieh, Yih-Dar^1,2  Chien, Yin-Hsiu^1,2,3  Tzen, Kai-Yuan^5,6,7  Yu, I-Shing^2,8  Chen, Pin-Wen^1,2  Hu, Min-Hsiu^1,2  Hu, Meng-kai^1,2  Muramatsu, Shin-ichi⁹  Ichinose, Hiroshi¹⁰  Hwu, Wuh-Liang^1,2,3 

[1] Natl Taiwan Univ Hosp, Dept Med Genet, Taipei 10041, Taiwan

[2] Natl Taiwan Univ, Coll Med, Taipei 10041, Taiwan

[3] Natl Taiwan Univ Hosp, Dept Pediat, Taipei 10041, Taiwan

[4] Natl Taiwan Univ, Grad Inst Clin Med, Coll Med, Taipei 10002, Taiwan

[5] Natl Taiwan Univ Hosp, Dept Nucl Med, Taipei 10002, Taiwan

[6] Natl Taiwan Univ, Coll Med, Taipei 10002, Taiwan

[7] Natl Taiwan Univ, Mol Imaging Ctr, Taipei 10764, Taiwan

[8] Natl Taiwan Univ Hosp, Taipei 10041, Taiwan

[9] Jichi Med Univ, Div Neurol, Dept Med, Shimotsuke, Tochigi 3290498, Japan

[10] Tokyo Inst Technol, Grad Sch Biosci & Biotechnol, Dept Life Sci, Yokohama, Kanagawa 2268501, Japan

关键词: Aromatic L-amino acid decarboxylase deficiency;    Mouse knock-in model;    Neurotransmitter;    Dopamine;    Serotonin;    Dyskinesia;    Splicing;   

DOI  :  10.1016/j.nbd.2012.12.005

来源: Elsevier

【 摘 要 】

Aromatic L-amino acid decarboxylase (AADC) is responsible for the syntheses of dopamine and serotonin. Children with AADC deficiency exhibit compromised development, particularly with regard to their motor functions. Currently, no animal model of AADC deficiency exists. We inserted an AADC gene mutation (IVS6+4A>T) and a neomycin-resistance gene into intron 6 of the mouse AADC (Ddc) gene. In the brains of homozygous knock-in (KO mice (Ddc(IVS6/IVS6)), AADC mRNA lacked exon 6, and AADC activity was <03% of that in wild-type mice. Half of the KI mice were born alive but grew poorly and exhibited severe dysldnesia and hindlimb clasping after birth. Two-thirds of the live-born KI mice survived the weaning period, with subsequent improvements in their growth and motor functions; however, these mice still displayed cardiovascular dysfunction and behavioral problems due to serotonin deficiencies. The brain dopamine levels in the KI mice increased from 9.39% of the levels in wild-type mice at 2 weeks of age to 37.86% of the levels in wild-type mice at 8 weeks of age. Adult KI mice also exhibited an exaggerated response to apomorphine and an elevation of striatal c-Fos expression, suggesting post-synaptic adaptations. Therefore, we generated an AADC deficient mouse model, in which compensatory regulation allowed the mice to survive to adulthood. This mouse model will be useful both for developing gene therapies for AADC deficiency and for designing treatments for diseases associated with neurotransmitter deficiency. (C) 2013 Elsevier Inc. All rights reserved.

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