Stress, caffeine and ethanol trigger transient neurological dysfunction through shared mechanisms in a mouse calcium channelopathy

• Type of Material: Article
• Authors: Robert S. Raike, Emory University; Catherine Weisz, Johns Hopkins University; Freek E. Hoebeek, Erasmus Medical Centre; Matthew C. Terzi, Emory University; Chris I. De Zeeuw, Erasmus Medical Centre; Arn M. van den Maagdenberg, Leiden University; Hyder A Jinnah, Emory University; Ellen Hess, Emory University
• Language: English
• Date: 2013-02-01
• Publisher: Elsevier
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2012 Elsevier Inc. All rights reserved.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.nbd.2012.09.005
• Title of Journal or Parent Work: Neurobiology of Disease
• ISSN: 0969-9961
• Volume: 50
• Issue: 1
• Start Page: 151
• End Page: 159
• Grant/Funding Information: This work was supported by the United States National Institutes of Health (R01 NS033592, R01 NS040470, F32 NS055584), the Dystonia Medical Research Foundation, ZonMW and the NeuroBasic-PharmaPhenomics consortium.
• Keywords: Neurosciences & Neurology; EPISODIC ATAXIA TYPE-2; RYANODINE RECEPTOR; MICE; Science & Technology; Neurosciences; Life Sciences & Biomedicine; Cerebellum; CA2+ RELEASE; CEREBELLAR PURKINJE NEURONS; Tottering; HEMIPLEGIC MIGRAINE; Calcium channel; PAROXYSMAL DYSKINESIAS; INTRACELLULAR STORES; Channelopathy; CORTICOTROPIN-RELEASING-FACTOR; MIDBRAIN DOPAMINE NEURONS; Episodic; Purkinje
• Research Categories: Biology, Genetics; Biology, Neuroscience; Health Sciences, Pharmacology

Abstract

Several episodic neurological disorders are caused by ion channel gene mutations. In patients, transient neurological dysfunction is often evoked by stress, caffeine and ethanol, but the mechanisms underlying these triggers are unclear because each has diverse and diffuse effects on the CNS. Attacks of motor dysfunction in the Ca V 2.1 calcium channel mouse mutant tottering are also triggered by stress, caffeine and ethanol. Therefore, we used the tottering mouse attacks to explore the pathomechanisms of the triggers. Despite the diffuse physiological effects of these triggers, ryanodine receptor blockers prevented attacks induced by all of them. In contrast, compounds that potentiate ryanodine receptors triggered attacks suggesting a convergent biochemical pathway. Tottering mouse attacks were both induced and blocked within the cerebellum suggesting that the triggers act locally to instigate attacks. In fact, stress, caffeine and alcohol precipitated attacks in Ca V 2.1 mutant mice in which genetic pathology was limited to cerebellar Purkinje cells, suggesting that the triggers initiate dysfunction within a specific brain region. The surprising biochemical and anatomical specificity of the triggers and the discovery that the triggers operate through shared mechanisms suggest that it is possible to develop targeted therapies aimed at blocking the induction of episodic neurological dysfunction, rather than treating the symptoms once provoked.