Mechanism of stress-induced attacks in an episodic neurologic disorder

Heather D. Snell, Ariel Vitenzon, Esra Tara, Chris Chen, Jaafar Tindi, Bryen A. Jordan, Kamran Khodakhah

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

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 tottering (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 α1-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 tottering 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.

Original languageEnglish (US)
Article numbereabh2675
JournalScience Advances
Volume8
Issue number16
DOIs
StatePublished - Apr 2022

ASJC Scopus subject areas

  • General

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