Cerebellar α1D- adrenergic receptors mediate stress-induced dystonia in totteringtg/tg mice.

Episodic ataxia type 2 (EA2) is an inherited neurological disorder, where patients suffer from chronic ataxia and severe episodes of motor dysfunction exhibited as dystonia. Despite other factors, physical and emotional stress triggers those episodes reliably in both human and mice. We used the well-established EA2 mouse model tottering to explore the cerebellar adrenergic receptor (AR) involvement in stress-induced dystonic attacks. We found that α1-ARs in cerebellar Purkinje cells (PCs) are activated by norepinephrine (NE), differentially expressed and required for initiation of dystonia, while α2-ARs are not. Moreover, pharmacological blockade and shRNA-induced knock down of cerebellar α1_D-ARs was sufficient to effectively prevent stress-induced dystonia in homozygous tottering^tg/tg mice but had no impact on ataxia amelioration. In vivo recordings and live calcium (Ca²⁺) imaging of PCs demonstrated that α1_D-AR blockade successfully protects PCs from NE-mediated erratic firing patterns through decreased release of Ca²⁺ from intracellular stores, thus preventing stress-induced dystonia. Together, our data show the modulatory effects of NE on dystonia severity and suggest a predominant role of cerebellar α1_D-ARs in the formation of stress-induced dystonia in tottering^tg/tg mice.