What Is the Role of Norepinephrine in Cerebellar Modulation and Stress-Induced Episodic Ataxia?

Abstract

The cerebellum receives noradrenergic input from the locus ceruleus (LC).1-3 The LC input to the cerebellar cortex is diffuse and targets mainly the molecular layer but also the Purkinje and granule cell layers.4,5 Norepinephrine (NE), acting through different adrenoceptor subtypes localized presynaptically and postsynaptically in the various components of the cerebellar circuit, has a complex modulatory effect on the tonic firing of Purkinje cells, which control the output of the cerebellum through the cerebellar nuclei (Figure). Purkinje cell activity is determined both by their intrinsic ion conductances and by synaptic influences from excitatory inputs from the mossy-parallel fiber and climbing fiber systems and inhibitory inputs from molecular layer interneurons.6,7 The components of the cerebellar cortex circuit express different α1-adrenergic, α2-adrenergic, and β-adrenergic receptor (adrenoceptors [ARs]) subtypes, with a distinct distribution.8,9 Given the multiple modulatory effects of NE in the cerebellar circuit, activation of LC and NE release in the cerebellum, for example, in response to stress, may directly or indirectly affect Purkinje cell activity and thus cerebellar output. Stress is an important trigger of episodic movement disorders due to channelopathies, including episodic ataxias (EAs).10 A common feature in several ataxic disorders is impaired tonic pacemaking firing of Purkinje cells.11-14 A recent study in the tottering mouse model of EA2 provides a mechanism by which stress, through the activation of LC-NE input to the cerebellum, can trigger episodic ataxia.15 This study supports the role of NE signaling and downstream effects on tonic firing of Purkinje cells and provides potential therapeutic approaches to treat this disorder. Furthermore, these results also provide a potential link between stress and other episodic movement disorders.