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

NEUROBIOLOGY OF DISEASE

卷:50

Article

Raike, Robert S.¹  Weisz, Catherine²  Hoebeek, Freek E.³  Terzi, Matthew C.⁴  De Zeeuw, Chris I.^3,5  van den Maagdenberg, Arn M.^6,8  Jinnah, H. A.^4,7  Hess, Ellen J.^1,4 

[1] Emory Univ, Sch Med, Dept Pharmacol, Atlanta, GA 30322 USA

[2] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21287 USA

[3] Erasmus MC, Dept Neurosci, NL-3015 GE Rotterdam, Netherlands

[4] Emory Univ, Sch Med, Dept Neurol, Atlanta, GA 30322 USA

[5] Netherlands Inst Neurosci, Royal Dutch Acad Arts & Sci, Amsterdam, Netherlands

[6] Leiden Univ, Med Ctr, Dept Human Genet, NL-2300 RC Leiden, Netherlands

[7] Emory Univ, Sch Med, Dept Human Genet, Atlanta, GA 30322 USA

[8] Leiden Univ, Med Ctr, Dept Neurol, NL-2300 RC Leiden, Netherlands

关键词: Episodic;    Channelopathy;    Cerebellum;    Purkinje;    Calcium channel;    Tottering;   

DOI  :  10.1016/j.nbd.2012.09.005

来源: Elsevier

【 摘 要 】

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. (C) 2012 Elsevier Inc. All rights reserved.

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