Alpha-Synuclein Oligomers Induce Glutamate Release From Astrocytes And Excessive Extrasynaptic Nmdar Activity In Neurons, Thus Contributing To Synapse Loss

Synaptic and neuronal loss are major neuropathological characteristics of Parkinson's disease. Misfolded protein aggregates in the form of Lewy bodies, comprised mainly of alpha-synuclein (alpha Syn), are associated with disease progression, and have also been linked to other neurodegenerative diseases, including Lewy body dementia, Alzheimer's disease, and frontotemporal dementia. However, the effects of alpha Syn and its mechanism of synaptic damage remain incompletely understood. Here, we show that alpha Syn oligomers induce Ca2+-dependent release of glutamate from astrocytes obtained from male and female mice, and that mice overexpressing alpha Syn manifest increased tonic release of glutamate in vivo. In turn, this extracellular glutamate activates glutamate receptors, including extrasynaptic NMDARs (eNMDARs), on neurons both in culture and in hippocampal slices of alpha Syn-overexpressing mice. Additionally, in patch-clamp recording from outside-out patches, we found that oligomerized alpha Syn can directly activate eNMDARs. In organotypic slices, oligomeric alpha Syn induces eNMDAR-mediated synaptic loss, which can be reversed by the drug NitroSynapsin. When we expose human induced pluripotent stem cell-derived cerebrocortical neurons to alpha Syn, we find similar effects. Importantly, the improved NMDAR antagonist NitroSynapsin, which selectively inhibits extrasynaptic over physiological synaptic NMDAR activity, protects synapses from oligomeric alpha Syn-induced damage in our model systems, thus meriting further study for its therapeutic potential.