Striatal spreading depolarization: Possible implication in levodopa‐induced dyskinetic‐like behavior

Abstract

A BS TRACT: Objective: Spreading depolarization (SD) is a transient self-propagating wave of neuronal and glial depolarization coupled with large membrane ionic changes and a subsequent depression of neuronal activity. Spreading depolarization in the cortex is implicated in migraine, stroke, and epilepsy. Conversely, spreading depolarization in the striatum, a brain structure deeply involved in motor control and in Parkinson's disease (PD) pathophysiology, has been poorly investigated. Methods: We characterized the participation of glutamatergic and dopaminergic transmission in the induction of striatal spreading depolarization by using a novel approach combining optical imaging, measurements of endogenous DA levels, and pharmacological and molecular analyses.Results: We found that striatal spreading depolarization requires the concomitant activation of D1-like DA and Nmethyl-D-aspartate receptors, and it is reduced in experimental PD. Chronic L-dopa treatment, inducing dyskinesia in the parkinsonian condition, increases the occurrence and speed of propagation of striatal spreading depolarization, which has a direct impact on one of the signaling pathways downstream from the activation of D1 receptors. Conclusion: Striatal spreading depolarization might contribute to abnormal basal ganglia activity in the dyskinetic condition and represents a possible therapeutic target.

Spreading depolarizations pose critical energy challenges in acute brain injury

“…Similarly, in the striatum, energy charge fell to 0.45–0.60 following injection of glutamate (1 mmol per 1 μL, a concentration of 1000 M) or NMDA (50 nmol in 1 μL, corresponding to a concentration of 50 mM) (Shepel et al, 2005). In this study, Shepel et al did not monitor for the occurrence of SD, but the striatum does support the initiation and propagation of SD (de Iure et al, 2019). The thresholds for induction of striatal SD by glutamate receptor agonists have yet to be established; in the cortex, 500 μM NMDA or 100 mM glutamate application can induce SD (Obrenovitch et al, 1994).…”

Пошук Цілей Терапії, Що Змінює Перебіг Хвороби Паркінсона

“…The prospects of studying the "autowave penumbra" are confirmed not only by the fact that some authors consider the similarity of the occurrence and propagation of depression waves in different animals as a property of the nervous system that has developed to control complex behavior that requires energy-consuming, fast information processing in a tightly regulated extracellular environment [30], which supports a systematic approach to understanding the electrophysiological basis of human neuropathology associated with migraine, stroke, and traumatic brain injury [30]. The prospects are also confirmed by the discovery of the connection of several electrophysiological phenomena with some clinical symptoms of amyotrophic lateral sclerosis (a fatal neurodegenerative disease) [31] and PD [23].…”

“…We name it as an electrophysiological target of therapy that changes the course of PD. Such electrophysiological phenomena as striatal spreading depolarization [23], spreading depression or spreading depolarization [24], cortical spreading depression [25] are actively studied in a number of neurological diseases [26], especially in elderly people [27,28].…”

Paroxysmal Genetic Movement Disorders and Epilepsy

“…• Increased predisposition to cortical spreading depolarization (depression), a known mechanism for hemiplegic migraine, as demonstrated in the Mashlool mouse (104). Notably, spreading depolarization exerts a modulatory effect on the function of the basal ganglia (105)(106)(107). In addition, spreading depression can occur in the basal ganglia and more directly lead to dysfunction of that system (108).…”