Mechanism of stress-induced attacks in an episodic neurologic disorder

Stress is the most common trigger among episodic neurologic disorders. In episodic ataxia type 2 (EA2), physical or emotional stress causes episodes of severe motor dysfunction that manifest as ataxia and dystonia. We used the (tg/tg) mouse, a faithful animal model of EA2, to dissect the mechanisms...

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Bibliographic Details
Published in:Science advances 2022-04, Vol.8 (16), p.eabh2675
Main Authors: Snell, Heather D, Vitenzon, Ariel, Tara, Esra, Chen, Chris, Tindi, Jaafar, Jordan, Bryen A, Khodakhah, Kamran
Format: Article
Language:English
Subjects:
Neuroscience
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Summary:Stress is the most common trigger among episodic neurologic disorders. In episodic ataxia type 2 (EA2), physical or emotional stress causes episodes of severe motor dysfunction that manifest as ataxia and dystonia. We used the (tg/tg) mouse, a faithful animal model of EA2, to dissect the mechanisms underlying stress-induced motor attacks. We find that in response to acute stress, activation of α -adrenergic receptors (α1-Rs) on Purkinje cells by norepinephrine leads to their erratic firing and consequently motor attacks. We show that norepinephrine induces erratic firing of Purkinje cells by disrupting their spontaneous intrinsic pacemaking via a casein kinase 2 (CK2)-dependent signaling pathway, which likely reduces the activity of calcium-dependent potassium channels. Moreover, we report that disruption of this signaling cascade at a number of nodes prevents stress-induced attacks in the mouse. Together, our results suggest that norepinephrine and CK2 are required for the initiation of stress-induced attacks in EA2 and provide previously unidentified targets for therapeutic intervention.
ISSN:2375-2548
2375-2548
DOI:10.1126/sciadv.abh2675