Microglial glutamate release evoked by α-synuclein aggregates is prevented by dopamine

MAURICIO DOS SANTOS PEREIRA; LEONARDO ACUÑA; SABAH HAMADAT; JEREMY ROCCA; FLORENCIA GONZALEZ-LIZÁRRAGA; ROSANA CHEHIN; JULIA E. SEPULVEDA-DIAZ; ELAINE DEL-BEL; RITA RAISMAN-VOZARI; PATRICK P. MICHEL

GLIA

WILEY-LISS, DIV JOHN WILEY & SONS INC

Lugar: New York; Año: 2018

0894-1491

Microglia, the resident immune cells of the brain, play a key role in inflammatory-type processes that contribute to neurodegeneration in Parkinson disease (PD). Microglial cell activation may be related to the aggregation process that affects the synaptic protein α-Synuclein (αS) in this pathology. In the present study, we aimed to (i) characterize the impact that aggregated forms of S may have on microglial cells, using glutamate release as a marker of the activation state of these cells and (ii) determine whether the neurotransmitter dopamine (DA) had the ability to modulate this process.Using a model system of post-natal microglial cells in culture, we established that aggregated but not monomeric forms of S had the capacity to robustly stimulate glutamate release in these cells. The stimulatory effect of S aggregates (Sa) on microglia was not observed in astrocytes. Glutamate release stimulation required concomitant activation of TLR2 and P2X7 receptors and relied on phosphoinositide 3-kinase (PI3K)-dependent signaling. Oxidative stress generated through NADPH oxidase appeared to be involved downstream to PI3K engagement and functioned as a key regulator of the effects of Sa on glutamate release. Blocking the Xc- antiporter system that accumulates extracellular L-cystine in exchange for glutamate, prevented glutamate release induced by Sa, indicating that the antiporter protein operated as final downstream effector for the effects of Sa. Most interestingly, glutamate release induced by Sa was also prevented by the neurotransmitter DA, which exerted its action through an antioxidant effect requiring activation of D1 DA receptor. Altogether, present data suggest that the activation of microglial cells by Sa may possibly result in a toxic build-up of extracellular glutamate contributing to excitotoxic stress in PD. The deficit in DA that characterizes this disorder may further aggravate this process in a vicious circle mechanism.