Research reveals new mechanism of paroxysmal dyskinesia

Recently, Cell Reports published an online research paper entitled "Cerebellar depolarization spreading mediates paroxysmal dyskinesia".
Completed by Xiong Zhiqi, a researcher at the laboratory and Shanghai Brain Science and Brain-like Research Center
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Studying model mice based on paroxysmal kinesigenic dyskinesia (PKD), using electrophysiological, calcium imaging, and behavioral analysis techniques to prove that mutations in the PKD pathogenic gene PRRT2 can cause depolarization of the cerebellar cortex Spreading depolarization is susceptible.
This discovery provides a new theory and experimental paradigm for the study of the neuropathological mechanism of PKD, and also provides a new idea for the treatment of PRRT2-related paroxysmal neurological diseases
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PKD is a paroxysmal neurological disease, which is mainly caused by a loss-of-function mutation in the PRRT2 gene
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Sudden movements or changes in body posture can induce involuntary movements in patients, manifested as hand dances, abnormal postures, athletes, throwing movements or other involuntary movements, which can last from a few seconds to tens of seconds
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In previous clinical studies, the onset symptoms of the disease have been comprehensively described, but the neuropathological mechanisms that mediate the occurrence, development and termination of involuntary movement disorders are still unknown
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In the process of systematically studying the pathological mechanism of paroxysmal dyskinesia, researchers found that the cerebellar cortex of PKD model mice is extremely susceptible to depolarization and spreading.
Different types of stimulation of cerebellar cortical granule cells can effectively induce depolarization.
The generation and propagation of spreading, and depolarizing spreading always occurs concurrently with the onset of dyskinesia
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Based on this discovery and the important role of the cerebellum in motor regulation, researchers put forward the hypothesis of "cerebellar depolarization spreading" for paroxysmal movement disorders for the first time (Figure 1)
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Depolarizing spreading or spreading depolarizing wave is a kind of tonic depolarizing event that can spread slowly in the gray matter area of ​​the brain induced by local stimulation under pathological conditions.
It is often accompanied by acute brain injury, cerebrovascular disease and acute migraine aura
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Previous studies have shown that the cerebral cortex and hippocampus are more susceptible to depolarization, while the cerebellar cortex is more resistant to this event
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At present, the cellular and molecular mechanisms that shape this characteristic of the cerebellar cortex have not been precisely elucidated
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This study shows that PRRT2 protein in cerebellar granule cells plays an important role in the process of cerebellar resistance to spreading depolarization
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PRRT2 protein delays the recovery of inactivated sodium ion channels and reduces their opening during repeated stimulation, thereby weakening the continuous excitability of neurons, thereby preventing local stimulation-induced depolarization and spreading in the cerebellar cortex
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Selective knockout of Prrt2 gene in mouse cerebellar cortex granular cells makes the cerebellar cortex in a state of depolarization and spreading susceptibility
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Further studies have shown that in Prrt2 knockout mice, the depolarizing wave will spread around the cerebellar cortex at a speed of 1.
5-3 mm/min from the trigger point, and make the extracellular potassium ion concentration in the passing area sharp.
Elevated, causing the cerebellar granule cells and Purkinje cells to undergo a long-term continuous depolarization, which eventually leads to a depolarization block of Purkinje cells and stops the regular action potential firing
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Purkinje cells are the main output neurons in the cerebellar cortex, and their nerve endings project to the cerebellar deep nuclei, forming the cerebellar Purkinje-deep nuclei loop
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Studies have shown that the depolarized spread of the cerebellum may seriously interfere with the normal activities of deep nucleus neurons through this loop, and lead to the occurrence of paroxysmal dyskinesia (Figure 2)
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The research work was funded by the Shanghai Municipal Commission of Science and Technology, the Chinese Academy of Sciences, the National Natural Science Foundation of China and the Ministry of Science and Technology
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Figure 1.
A schematic diagram of the slow spread of depolarizing waves in the mouse cerebellar cortex
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Figure 2.
The absence or functional defect of PRRT2 can make the cerebellar cortex susceptible to depolarization spreading by enhancing the function of sodium ion channels
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The spread of depolarization in the cerebellar cortex interferes with the function of the cerebellar Purkinje-deep nucleus loop and eventually leads to paroxysmal dyskinesia.
Source: Center for Excellence in Brain Science and Intelligent Technology, Chinese Academy of Sciences