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Mechanism of stress-induced attacks in an episodic neurologic disorder.

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.

SUBMITTER: Snell HD

PROVIDER: S-EPMC9020779 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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Mechanism of stress-induced attacks in an episodic neurologic disorder.

Snell Heather D HD Vitenzon Ariel A Tara Esra E Chen Chris C Tindi Jaafar J Jordan Bryen A BA Khodakhah Kamran K

Science advances 20220420 16

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 <i>tottering</i> (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<sub>1</sub>-adrenergic receptors (α1-Rs) on Purkinje cells by norepinephrine leads t ...[more]

PMID: 35442745

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Mechanism of stress-induced attacks in an episodic neurologic disorder.

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Mechanism of stress-induced attacks in an episodic neurologic disorder.

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