Science sub-journal: Stress costs the cerebellum?

Click the blue word to follow us Stress (stress) is one of the most common triggers of episodic neurological disorders such as epilepsy, migraines and movement disorders
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Episodic ataxia type 2 (EA2) is an autosomal dominant channel disorder caused by mutations in the gene CACNA1A, which encodes a P/Q-type voltage-dependent calcium channel
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Coffee, alcohol, and physical or emotional stress can cause severe ataxia and dystonia episodes
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Toddler mice (tg/tg mice) are a typical EA2 animal model, which manifests as abnormal gait, retardation, dystonia, ataxia and other movement disorders
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Stress or caffeine can induce motor dysfunction in staggering mice by inducing burst firing activity in cerebellar Purkinje cells
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This cluster discharge activity may be caused by increased norepinephrine release and activation of α1-adrenergic receptors
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April 20, 2022 The research team of Kamran Khodakhah at the Albert Einstein College of Medicine has revealed the molecular mechanism of the onset of stress-induced dyskinesias
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Figure 1: High-frequency cluster firing activity in the cerebellum during seizures in waddling mice The researchers found that chronic restraint stress induced high-frequency cluster discharge activity in the cerebellum of the waddling mice, and the number of dyskinesia seizures increased
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Intraperitoneal or intracerebellar injection of the α1-adrenergic receptor antagonist prazosin reduces stress-induced episodes of dyskinesia
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Injecting norepinephrine or α1-adrenergic receptor agonists into the cerebellum can increase the onset of dyskinesia in wobbling mice, suggesting that stress-induced dyskinesia onset is dependent on adrenergic signaling
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Norepinephrine can enhance the rapid burst discharge activity of Purkinje cells in normal and rambling mice, and α1-adrenergic receptor antagonists can block the abnormal discharge activity caused by norepinephrine
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Figure 2: Photoactivation of locus coeruleus neurons promotes the onset of dyskinesia.
Studies have shown that cerebellar noradrenergic inputs receive projections from locus coeruleus neurons, and electrical stimulation of the locus coeruleus increases cerebellar norepinephrine concentrations
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Activation of locus coeruleus neurons by optogenetic techniques promotes the onset of dyskinesia in wobbling mice, and intracerebellar injection of α1-adrenergic receptor antagonists can reduce the number of seizures, further indicating that stress-induced dyskinesia onset is dependent on epinephrine energy signal
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Studies have shown that norepinephrine can activate α1-adrenergic receptors and reduce the activity of small-conductance calcium-activated potassium channels (SK channels)
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Acute activation of SK channel activity can rapidly abort the onset of caffeine-induced dyskinesia
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Here, we found that the cerebellum of staggering mice was exacerbated by dyskinesia after receiving SK channel blockers
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Casein kinase 2 (CK2)-dependent phosphorylation of calmodulin reduces SK channel opening
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Immunofluorescence showed that stress can increase the level of cerebellar calmodulin phosphorylation, which can be significantly attenuated by inhibiting CK2 activity or by viral knockdown of CK2 expression
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Collectively, this paper reveals the mechanism by which stress induces episodic ataxia: stress promotes cerebellar norepinephrine release, which subsequently activates α1-adrenergic receptors, and ultimately inhibits SK channel activity to induce ataxia episodes
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[Reference] 1.
Mechanism of stress-induced attacks in an episodic neurologic disorder The pictures in the text are from the reference