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| New mechanism of cerebellar depolarization "storm" paroxysmal dyskinesia was discovered |
Based on the model mice of paroxysmal motor-induced dyskinesia (PKD), the Xiong Zhiqi research group of the Center for Excellence in Brain Science and Intelligent Technology of the Chinese Academy of Sciences (Institute of Neuroscience) used electrophysiology, calcium imaging, and behavioral analysis to prove Mutations in the PKD pathogenic gene PRRT2 can cause the cerebellar cortex to be susceptible to depolarization.
This discovery provides a new theory and experimental paradigm for the study of the neuropathological mechanism of PKD, as well as the treatment of PRRT2-related paroxysmal neurological diseases New ideas
.
On September 21, the research results were published online in Cellular Communications
PKD is a paroxysmal neurological disease, which is mainly caused by a loss-of-function mutation in the PRRT2 gene
.
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
In the process of systematically studying the pathological mechanism of paroxysmal dyskinesia, the 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 occur concurrently with the onset of dyskinesia
.
Based on this discovery and the important role of the cerebellum in motor regulation, the research team first proposed the hypothesis of "cerebellar depolarization spread" for paroxysmal dyskinesia
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
.
Previous studies have shown that the cerebral cortex and hippocampus are more susceptible to depolarization, while the cerebellar cortex is highly resistant to this event
This work shows that PRRT2 protein in cerebellar granule cells plays an important role in the process of cerebellar resistance to spreading depolarization
.
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
Further studies have shown that in Prrt2 knockout mice, the depolarization 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, and finally causing Purkinje cells to depolarize and stop the regular action potential firing
.
Purkinje cells are the main output neurons of the cerebellar cortex, and their nerve endings project to the deep nucleus of the cerebellum, forming the Purkinje-deep nucleus loop of the cerebellum
Experts said that studies have shown that the depolarization and spreading of the cerebellum may severely interfere with the normal activities of deep nucleus neurons through this loop, and cause paroxysmal movement disorders
.
(Source: Huang Xin, China Science News)
Related paper information: https://doi.
https://doi.
org/10.
1016/j.
celrep.
2021.
109743
