Adrenergic receptor activation triggers stress-induced dystonia in a CACNA1A mutant mouse model

Episodic ataxia type 2 (EA2) is caused by loss-of-function mutations in CACNA1A, resulting in P/Q-type Ca²⁺ channel dysfunction in cerebellar Purkinje cells (PCs) causing ataxia and stress-induced dystonia. Using Cacna1a^purk(-/-) (<i>purky</i>) mice, which display selective P/Q-type channels deletion in PCs, the effects of adrenergic receptor (AR) blockade on stress-induced dystonia were examined. Systemic administration of the α1-AR antagonist prazosin increased dystonia frequency, but shortened attack duration, while the α1D-AR selective antagonist BMY-7378 significantly reduced dystonia occurrence without altering onset or duration. Strikingly, universal blockade of α2-ARs using yohimbine, as well as agonist of α2A-AR autoreceptors completely abolished stress-induced dystonia. Electrophysiological recordings of cerebellar PCs demonstrated that norepinephrine (NE) strongly inhibited the PC simple spike firing, which was partially rescued by yohimbine, implicating α2-AR-dependent modulation of PC activity. Histological analysis of <i>purky</i> mice revealed increased dopamine-<i>β</i>-hydroxylase (DβH) immunoreactivity on PC somata, which was accompanied by increased numbers of noradrenergic neurons in locus coeruleus (LC), indicating enhanced cerebellar noradrenergic innervation. These findings strengthen the idea that stress-induced dystonia formation is facilitated by increased noradrenergic innervation to cerebellar PCs and suggest that α2-AR signalling contributes to dystonia in EA2. Our findings emphasise cerebellar ARs as promising therapeutic targets in EA2.