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.

Cerebellar α1D-adrenergic receptors mediate stress-induced dystonia in totteringtg/tgmice

“…The mechanism, how blockade of α1-ARs prevents stress-induced attacks of motor dysfunction was recently postulated ( 73 , 74 ). Snell et al showed that NE binding to α1-ARs results in a reduced open probability of small conductance K + channels (SK) through phosphorylation of SK-associated calmodulin (CaM) through SK2-associated casein kinase 2 (CK2) ( 21 ).…”

“…Especially prazosin was shown to cause headache, dizziness, palpitation and tachycardia ( 84 , 85 ). Development and further exploration of α1 D -AR specific drugs may not only be beneficial for EA2 patients, but for all patients suffering from episodic neurological disorders where stress is a common trigger ( 74 ). The α1 D -AR may provide a more specific therapeutic target in treating episodic neurological disorders.…”

C9ORF72 patient-derived endothelial cells drive blood-brain barrier disruption and contribute to neurotoxicity

“…The other main component of the BBB is the astrocyte [6], which plays an essential role in establishing and maintaining it. Astrocytic end-feet form a coating network around the brain vasculature, the glia limitans, and, together with endothelial cells and pericytes [7], they form the BBB, separating the bloodstream from the brain parenchyma. All components interact with each other, contributing to BBB function, development, and maintenance [4].…”