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Dopamine dysregulation in a mouse model of paroxysmal nonkinesigenic dyskinesia
Hsien-yang Lee, … , Robert H. Edwards, Louis J. Ptácek
Hsien-yang Lee, … , Robert H. Edwards, Louis J. Ptácek
Published January 3, 2012
Citation Information: J Clin Invest. 2012;122(2):507-518. https://doi.org/10.1172/JCI58470.
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Research Article Neuroscience Article has an altmetric score of 2

Dopamine dysregulation in a mouse model of paroxysmal nonkinesigenic dyskinesia

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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 5

In vivo microdialysis of Pnkd mice.

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In vivo microdialysis of Pnkd mice.
(A) Striatal dopamine concentrations...
(A) Striatal dopamine concentrations were measured by no net flux microdialysis (mut-Tg, n = 7; WT, n = 5). Decreased levels of extracellular dopamine were observed in striata of Pnkd mice (P < 0.005). ** P < 0.01. (B) No significant difference in extraction fractions was found between genotypes. (C) Dopamine concentrations at basal levels and after stress/caffeine stimulation were reduced in striata of Pnkd mice (P < 0.005, n = 7) versus controls (n = 5). (D) Higher levels of dopamine release in response to stress and caffeine injection were observed in striata of Pnkd versus WT mice (P < 0.05). All data are shown as mean ± SEM.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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