Impaired striatal dopamine output of homozygous Wfs1 mutant mice in response to [K + ] challenge
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ORIGINAL ARTICLE
Impaired striatal dopamine output of homozygous Wfs1 mutant mice in response to [K+] challenge Vallo Matto & Anton Terasmaa & Eero Vasar & Sulev Kõks
Received: 12 January 2010 / Accepted: 21 September 2010 / Published online: 23 October 2010 # University of Navarra 2010
Abstract Loss of function of the Wfs1 gene causes Wolfram syndrome, a rare multisystem degenerative disorder. Mutant mice with targeted Wfs1 gene disruption (Wfs1 KO) display morphological and behavioral impairments that are not well understood. The present study aimed to investigate the striatal dopamine output of wild-type, heterozygous, and homozygous Wfs1 null-mutant mice using in vivo microdialysis technique. The baseline dopamine output in striatum was similar in all three animal groups. The application of 100 mM [K+]-rich modified Ringer solution caused in homozygous Wfs1 mutant mice an increase of dopamine output by 400%, while in wildtype and heterozygous animals, the increase of the dopamine output yielded up to 1,200%. In sum, the homozygous Wfs1 mutant mice (AUC 0 – 3 = 0.212 nM/μl h) show significantly decreased striatal V. Matto (*) Department of Pharmacy, University of Tartu, Ülikooli 18, 50090 Tartu, Estonia e-mail: [email protected] V. Matto : A. Terasmaa : E. Vasar : S. Kõks Department of Physiology, University of Tartu, Ülikooli 18, 50090 Tartu, Estonia A. Terasmaa : E. Vasar : S. Kõks Centre of Excellence for Translational Medicine, University of Tartu, Ülikooli 18, 50090 Tartu, Estonia
dopamine output in response to high-concentration [K +] challenge as compared with wild-type or heterozygous Wfs1 mutant conspecifics (AUC0–3 = 0.427 and 0.505 nM/μl h, respectively). This could explain at least some of the behavioral alterations in Wfs1 mutant mice. Keywords Wfs1 . Wolfram syndrome . Transgenic mice . Dopamine . Striatum . In vivo microdialysis . Mice
Introduction In 1938, Wolfram and Wagener [27] described for the first time a syndrome associated with a complex of moderate-to-severe progressive symptoms/conditions such as diabetes insipidus, diabetes mellitus, optic atrophy, and deafness (referred also as the DIDMOAD syndrome) [23]. In addition to the endocrine symptoms listed, the Wolfram syndrome may also include several neuropsychological phenomena, while the mood disorders and impulsive behavior tend to prevail [24]. It is widely accepted that the true Wolfram syndrome is a rare inherited disorder caused by the loss-of-function mutations in the Wfs1 gene, and its prevalence is estimated to be only 1/770,000 of the population [5]. Though the hallmark of the Wolfram syndrome is the gradual loss of the pancreatic beta cell islets [7, 8] which leads to the aggravation of the endocrine status, the neurodegenerative findings
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implicated to the Wolfram syndrome have been repeatedly reported too [6]. Furthermore, although the defective Wfs1 gene seems to be crucially associated with both endocrine and CNS phenomena, the link between these systems is still unknown [11]. Knockout (KO) animal models serve as in
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