A-Synuclein oligomers induce glutamate release from astrocytes and excessive extrasynaptic nmdar activity in neurons, thus contributing to synapse loss

Abstract

Synaptic and neuronal loss are major neuropathological characteristics of Parkinson's disease. Misfolded protein aggregates in the form of Lewy bodies, comprised mainly of a-synuclein (aSyn), 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 aSyn and its mechanism of synaptic damage remain incompletely understood. Here, we show that aSyn oligomers induce Ca21-dependent release of glutamate from astrocytes obtained from male and female mice, and that mice overexpressing aSyn 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 aSyn-overexpressing mice. Additionally, in patch-clamp recording from outside-out patches, we found that oligomerized aSyn can directly activate eNMDARs. In organotypic slices, oligomeric aSyn 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 aSyn, we find similar effects. Importantly, the improved NMDAR antagonist NitroSynapsin, which selectively inhibits extrasynaptic over physiological synaptic NMDAR activity, protects synapses from oligomeric aSyn-induced damage in our model systems, thus meriting further study for its therapeutic potential.