Dopamine dysregulation in a mouse model of paroxysmal nonkinesigenic dyskinesia

• Type of Material: Article
• Authors: Hsien-Yang Lee, University of California San Francisco; Junko Nakayama, University of California San Francisco; Ying Xu, University of California San Francisco; Xueliang Fan, Emory University; Maha Karouani, Tufts University; Yiguo Shen, University of California San Francisco; Emmanuel N. Pothos, Tufts University; Ellen Hess, Emory University; Ying-Hui Fu, University of California San Francisco; Robert H. Edwards, University of California San Francisco; Louis J. Ptacek, University of California San Francisco
• Language: English
• Date: 2012-02-01
• Publisher: American Society for Clinical Investigation
• Publication Version: Final Published Version
• Copyright Statement: © 2012, American Society for Clinical Investigation
• Final Published Version (URL): http://dx.doi.org/10.1172/JCI58470
• Title of Journal or Parent Work: Journal of Clinical Investigation
• ISSN: 0021-9738
• Volume: 122
• Issue: 2
• Start Page: 507
• End Page: 518
• Grant/Funding Information: This work was supported by grants from the Dystonia Medical Research Foundation, the Bachmann-Strauss Dystonia & Parkinson Foundation, NIH grant U54 RR19481, the Sandler Neurogenetics Fund, and P30 NS047243 (Tufts Center for Neuroscience Research).
• Keywords: RAT MODEL; GENE; Medicine, Research & Experimental; BASAL GANGLIA; Science & Technology; Research & Experimental Medicine; MYOFIBRILLOGENESIS REGULATOR-1; Life Sciences & Biomedicine; DYSTONIC CHOREOATHETOSIS; PARKINSONS-DISEASE; RECEPTOR INTERACTIONS; ADENOSINE; CHROMOSOME 2Q; NON-KINESIGENIC DYSKINESIA; MEDICINE, RESEARCH & EXPERIMENTAL
• Research Categories: Health Sciences, Pharmacology; Biology, Neuroscience

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 cfos 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. Copyright © 2012, American Society for Clinical Investigation.