Regulation of the dopaminergic system in a murine model of aromatic l-amino acid decarboxylase deficiency
Journal
Neurobiology of Disease
Journal Volume
52
Pages
177-190
Date Issued
2013
Author(s)
Shieh Y.-D.
KAI-YUAN TZEN
Yu I.-S.
Chen P.-W.
Hu M.-H.
Hu M.-K.
Muramatsu S.-I.
Ichinose H.
Abstract
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 (KI) mice (DdcIVS6/IVS6), AADC mRNA lacked exon 6, and AADC activity was <. 0.3% of that in wild-type mice. Half of the KI mice were born alive but grew poorly and exhibited severe dyskinesia 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. ? 2013 Elsevier Inc.
SDGs
Other Subjects
apomorphine; aromatic levo amino acid decarboxylase; dopamine; messenger RNA; protein c fos; serotonin; animal behavior; animal experiment; animal model; animal tissue; aromatic levo amino acid decarboxylase gene; article; cardiovascular disease; controlled study; disease severity; DNA sequence; dopamine brain level; dopaminergic system; dyskinesia; enzyme activity; enzyme deficiency; excitability; exon; female; gene insertion; intron; motor dysfunction; mouse; mutator gene; neuromodulation; neurotransmission; nonhuman; nucleotide sequence; postsynaptic potential; priority journal; protein expression; upregulation; Amino Acid Metabolism, Inborn Errors; Animals; Aromatic-L-Amino-Acid Decarboxylases; Disease Models, Animal; Dopamine; Dyskinesias; Gene Knock-In Techniques; Mice; Neostriatum
Type
journal article