Dopamine dysregulation in a mouse model of paroxysmal nonkinesigenic dyskinesia
Hsien-yang Lee, Junko Nakayama, Ying Xu, Xueliang Fan, Maha Karouani, Yiguo Shen, Emmanuel N. Pothos, Ellen J. Hess, Ying-Hui Fu, Robert H. Edwards, Louis J. Ptácek
Hsien-yang Lee, Junko Nakayama, Ying Xu, Xueliang Fan, Maha Karouani, Yiguo Shen, Emmanuel N. Pothos, Ellen J. Hess, Ying-Hui Fu, Robert H. Edwards, Louis J. Ptácek
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Research Article Neuroscience

Dopamine dysregulation in a mouse model of paroxysmal nonkinesigenic dyskinesia

Abstract

Paroxysmal nonkinesigenic dyskinesia (PNKD) is an autosomal dominant episodic movement disorder. Patients have episodes that last 1 to 4 hours and are precipitated by alcohol, coffee, and stress. Previous research has shown that mutations in an uncharacterized gene on chromosome 2q33–q35 (which is termed PNKD) are responsible for PNKD. Here, we report the generation of antibodies specific for the PNKD protein and show that it is widely expressed in the mouse brain, exclusively in neurons. One PNKD isoform is a membrane-associated protein. Transgenic mice carrying mutations in the mouse Pnkd locus equivalent to those found in patients with PNKD recapitulated the human PNKD phenotype. Staining for c-fos demonstrated that administration of alcohol or caffeine induced neuronal activity in the basal ganglia in these mice. They also showed nigrostriatal neurotransmission deficits that were manifested by reduced extracellular dopamine levels in the striatum and a proportional increase of dopamine release in response to caffeine and ethanol treatment. These findings support the hypothesis that the PNKD protein functions to modulate striatal neuro­transmitter release in response to stress and other precipitating factors.

Authors

Hsien-yang Lee, Junko Nakayama, Ying Xu, Xueliang Fan, Maha Karouani, Yiguo Shen, Emmanuel N. Pothos, Ellen J. Hess, Ying-Hui Fu, Robert H. Edwards, Louis J. Ptácek

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Figure 4

Pnkd mutant mice (mut-Tg, Pnkd mice) recapitulate the PNKD phenotype and have altered dopamine signaling.

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Pnkd mutant mice (mut-Tg, Pnkd mice) recapitulate the PNKD phenotype an...
(A) Quantifying activity of Pnkd mice and WT littermates after caffeine injection (25 mg/kg, i.p.). Caffeine-induced hyperkinetic movements in mutant mice. (B) Activity ratings of Pnkd mice and WT littermates after saline injection (10 ml/kg, i.p.). A slight increase in activity was observed in Pnkd mice 30–50 minutes after saline injection. (C) The mut-Tg mice manifested profound dyskinesia after injection of ethanol (1.5 g/kg, 20% v/v, i.p.), but the same treatment failed to induce hyperkinetic movements in WT littermates. Activity ratings are expressed as mean ± SEM (n = 8 for each group). (D) There were no obvious differences in the dopamine levels in striatal extracts from mice of various genotypes at rest or after caffeine treatment. (E and F) Both DOPAC levels and DOPAC/dopamine ratios were significantly increased in Pnkd mice (P < 0.01) after caffeine treatment, but decreased in WT and KO mice (P < 0.01). (G) The HVA levels at rest versus after caffeine treatment were significantly increased in Pnkd mice (P < 0.05). All data are presented as mean ± SEM. *P < 0.05; **P < 0.01.