Cerebellar Depolarization ‘Storm’in an Animal Model of PKD Disease--Center for Excellence in Brain Science and Intelligence Technology

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Cerebellar Depolarization ‘Storm’in an Animal Model of PKD Disease

Time：2021-09-22

A recent study published in Cell Reports demonstrated that the deficiency of PRRT2 facilitates the induction of cerebellar spreading depolarization (SD), which mediates paroxysmal movement disorder. This work was performed by Dr. XIONG Zhiqi’s Lab at the Institute of Neuroscience, State Key Laboratory of Neuroscience, Center for Excellence in Brain Sciences and Intelligence Technology of the Chinese Academy of Sciences. The findings in this work uncover a pivotal role of cerebellar SD in paroxysmal dyskinesia, providing a potent target for treating PRRT2-related paroxysmal disorders.

Paroxysmal kinesigenic dyskinesia (PKD) is the most common form of paroxysmal dyskinesia, characterized by sudden attacks of dystonia, chorea, or other involuntary movements. It is often precipitated by sudden changes in movements, and lasts for seconds to tens of seconds each time. The PRRT2 has been identified as a major causative gene for PKD disease at 2011, however, how the deficiency of PRRT2 protein causes paroxysmal dyskinetic movements have remained elusive. The researchers from XIONG’s Lab found that, in Prrt2-deficient mice, cerebellar SD was invariably accompanied by an attack of dyskinesia. In light on this finding and the essential role of the cerebellum in motor coordination, the researchers hypothesized that the induction of SD in the cerebellum potentially mediates the paroxysmal dyskinesia in an animal model of PKD (Figure 1).

Figure 1. Illustration showing the SD propagates in the cerebellar cortex of Prrt2 mutant mice.（Image by CEBSIT）

Spreading depolarization is a slowly propagated wave of neuronal and glial depolarization in the gray matter, accompanied by a near-complete breakdown of neuronal transmembrane ionic gradients, excessive neurotransmitter release and neuronal swelling. It has been implicated in the pathophysiology of several brain diseases, including subarachnoid hemorrhage, ischemia, stroke, and migraine aura. In rodents, comparing to the cerebral cortex and hippocampus, the cerebellum is resistant to SD in its normal state, although the molecular and cellular mechanisms underlying this resistance are unclear.

In this study, researchers found that the PRRT2 could reduce the availability of Nav channels by slowing the recovery of these channels from inactivation. This effect of PRRT2 decreased the neuronal excitability of cerebellar granule cells, contributing to the resistance of the cerebellum to SD. Meanwhile, the researchers found that the deficiency of PRRT2 facilitated the induction of SD in the cerebellum. In Prrt2-deficient mice, local stimulation on cerebellar cortex induced SD that propagated at speed of 1.5 – 3 mm/min in the gray matter, depolarizing a large population of cerebellar granule cells and Purkinje cells. Electrophysiological recordings further revealed that cerebellar SD blocked Purkinje cell spiking and disturbed neuronal firing of the deep cerebellar nuclei (DCN), and the resultant aberrant firing patterns in DCN were tightly, temporally coupled to dyskinetic episodes in Prrt2-deficient mice (Figure 2).

Figure 2. The mechanism underlying paroxysmal dyskinesia in prrt2-deficient mice. （Image by CEBSIT）

In this research, the identification of cerebellar SD as an instigator for Prrt2-associated paroxysmal dyskinesia has significant implications for understanding the pathological mechanisms of PKD and can inform the development of therapies for PRRT2-associated neurological disorders. Vice versa, it also has significant implications for understanding the mechanisms and functions of the SD.

This work entitled “Cerebellar spreading depolarization mediates paroxysmal movement disorder” was published online in Cell Reports on the 21th, September, 2021. LU Bin, LOU Sensen, XU Ruoshui, KONG Delun, WU Rongjie and ZHANG Jing from Dr. XIONG’s Lab are co-first authors. ZHUANG Ling and HE Jun-Yan at the Brain Sciences and Intelligence Technology of the Chinese Academy of Sciences, WU Xuemei at ShanghaiTech University and Prof. WU Zhiying at the Zhejiang University School of Medicine contributed to this work. This work also benefited from the kind help from other Labs and facilities of the Brain Sciences and Intelligence Technology of the Chinese Academy of Sciences. This project was supported by grants from Shanghai Municipal Government, Ministry of Science and Technology of the People′s Republic of China, National Natural Science Foundation of China and Chinese Academy of Sciences.

AUTHOR CONTACT:

XIONG Zhiqi

Center for Excellence in Brain Science and Intelligence Technology (Institute of Neuroscience), Chinese Academy of Sciences, Shanghai, China.

Email: xiongzhiqi@ion.ac.cn

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