Cerebellar spreading depolarization mediates paroxysmal movement disorder

Lu, Bin; Lou, Sen-Sen; Xu, Ruo-Shui; Kong, De-Lun; Wu, Rongjie; Zhang, Jing; Zhuang, Ling; Wu, Xuemei; He, Jinlan; Wu, Zhi‐Ying; Xiong, Zhi‐Qi

doi:10.1016/j.celrep.2021.109743

Cited by 20 publications

(34 citation statements)

References 76 publications

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“…With further experimentation, the team was able to find that the inactivation of sodium channels was sufficient to block cerebellar SD. This result may help to explain the effectiveness of carbamazepine in the treatment of PKD [18]. The effectiveness of carbamazepine in treating the symptoms of our PNKD patient may suggest that similar pathophysiology may be implicated between PNKD and PKD, although future research should focus on elucidating the role of SD in the pathologic process of the various PD subtypes.…”

Section: Discussionmentioning

confidence: 67%

“…As expected from the similar phenotype across different PD subtypes, the different genetic mutations all converge into a limited range of pathologic pathways that ultimately leads to neurotransmission disruption, mostly in the cerebellar and striatal circuits [17]. A recent study by Lu et al further elucidates this mechanism by drawing an association between PRRT2 deficiency and increased induction of cerebellar spreading depolarization (SD), demonstrating that SD can cause a depolarization block of Purkinje cells and disturb cerebellar outputs, leading to dyskinetic movements in PKD [18]. The study also confirmed the effect of the PRRT2 mutation on the SNARE complex and the voltage-gated sodium channels.…”

Section: Discussionmentioning

confidence: 99%

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Paroxysmal Non-Kinesigenic Choreoathetosis Case Report and a Review of the Pathogenesis

Kara¹,

Park²,

Lallani³

et al. 2022

Cureus

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Paroxysmal dyskinesias are a rare group of episodic movement disorders characterized by any combination of dystonia, chorea, and athetosis. Patients usually present early in life with episodes of variable frequency involving the limbs or facial muscles that can be disabling. In this article, we present a case of paroxysmal non-kinesigenic dyskinesia that was responsive to the sodium-channel blocker carbamazepine. Recent data has revealed the role of voltage-gated sodium channels in the pathophysiology of the disease; hence, these disorders are referred to as channelopathies. Further advancements in genetic analysis have elucidated targets corresponding to these disorders, indicating a possible role for gene sequencing in helping to differentiate the subtypes of paroxysmal dyskinesias. This case report sheds light on the pathophysiology of the various channelopathies, especially the findings of cerebellar spreading depolarization and its implication in paroxysmal kinesigenic and non-kinesigenic dyskinesias.

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Section: Discussionmentioning

confidence: 67%

Section: Discussionmentioning

confidence: 99%

Paroxysmal Non-Kinesigenic Choreoathetosis Case Report and a Review of the Pathogenesis

Kara¹,

Park²,

Lallani³

et al. 2022

Cureus

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“…Spreading depolarization is one of the most important pathophysiological processes of the CNS, with far-reaching implications for neurology, and there, not only for migraine with aura, but also for the most diverse forms of acute injury of the cerebrum and most likely also of the cerebellum, brainstem and spinal cord, and even for paroxysmal movement disorders ( Lu et al, 2021 ). Spreading depolarization is among the most basic pathological processes in the nervous system that appeared in phylogenesis even before the development of a proper blood circulation ( Spong et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

Migraine Aura, Transient Ischemic Attacks, Stroke, and Dying of the Brain Share the Same Key Pathophysiological Process in Neurons Driven by Gibbs–Donnan Forces, Namely Spreading Depolarization

Lemâle

Lückl

Horst

et al. 2022

Front. Cell. Neurosci.

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Neuronal cytotoxic edema is the morphological correlate of the near-complete neuronal battery breakdown called spreading depolarization, or conversely, spreading depolarization is the electrophysiological correlate of the initial, still reversible phase of neuronal cytotoxic edema. Cytotoxic edema and spreading depolarization are thus different modalities of the same process, which represents a metastable universal reference state in the gray matter of the brain close to Gibbs–Donnan equilibrium. Different but merging sections of the spreading-depolarization continuum from short duration waves to intermediate duration waves to terminal waves occur in a plethora of clinical conditions, including migraine aura, ischemic stroke, traumatic brain injury, aneurysmal subarachnoid hemorrhage (aSAH) and delayed cerebral ischemia (DCI), spontaneous intracerebral hemorrhage, subdural hematoma, development of brain death, and the dying process during cardio circulatory arrest. Thus, spreading depolarization represents a prime and simultaneously the most neglected pathophysiological process in acute neurology. Aristides Leão postulated as early as the 1940s that the pathophysiological process in neurons underlying migraine aura is of the same nature as the pathophysiological process in neurons that occurs in response to cerebral circulatory arrest, because he assumed that spreading depolarization occurs in both conditions. With this in mind, it is not surprising that patients with migraine with aura have about a twofold increased risk of stroke, as some spreading depolarizations leading to the patient percept of migraine aura could be caused by cerebral ischemia. However, it is in the nature of spreading depolarization that it can have different etiologies and not all spreading depolarizations arise because of ischemia. Spreading depolarization is observed as a negative direct current (DC) shift and associated with different changes in spontaneous brain activity in the alternating current (AC) band of the electrocorticogram. These are non-spreading depression and spreading activity depression and epileptiform activity. The same spreading depolarization wave may be associated with different activity changes in adjacent brain regions. Here, we review the basal mechanism underlying spreading depolarization and the associated activity changes. Using original recordings in animals and patients, we illustrate that the associated changes in spontaneous activity are by no means trivial, but pose unsolved mechanistic puzzles and require proper scientific analysis.

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“…A large body of experimental data have contributed to the understanding of PRRT2 function and pathogenesis of paroxysmal disorders associated with loss-of-function mutations in PRRT2 , that has been described as a network stability gene ( 16 , 17 ). We and other groups have found that genetic deletion of the PRRT2 gene in the mouse (PRRT2KO) mimics the human pathology and displays network hyperexcitability particularly in brain areas where PRRT2 is highly expressed, such as the cerebellum and the hippocampus ( 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ). Physiological levels of PRRT2 seem to be necessary to maintain a normal level of network activity, so that an overexpression of PRRT2, occurring in the 16p11.2 duplication, is also associated with neuropsychiatric disorders including epilepsy ( 26 ).…”

mentioning

confidence: 99%

The intramembrane COOH-terminal domain of PRRT2 regulates voltage-dependent Na+ channels

Franchi¹,

Marte²,

Corradi³

et al. 2023

Journal of Biological Chemistry

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Cerebellar spreading depolarization mediates paroxysmal movement disorder

Cited by 20 publications

References 76 publications

Paroxysmal Non-Kinesigenic Choreoathetosis Case Report and a Review of the Pathogenesis

Paroxysmal Non-Kinesigenic Choreoathetosis Case Report and a Review of the Pathogenesis

Migraine Aura, Transient Ischemic Attacks, Stroke, and Dying of the Brain Share the Same Key Pathophysiological Process in Neurons Driven by Gibbs–Donnan Forces, Namely Spreading Depolarization

The intramembrane COOH-terminal domain of PRRT2 regulates voltage-dependent Na+ channels

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