| First Author | Trudler D | Year | 2021 |
| Journal | J Neurosci | Volume | 41 |
| Issue | 10 | Pages | 2264-2273 |
| PubMed ID | 33483428 | Mgi Jnum | J:304777 |
| Mgi Id | MGI:6511128 | Doi | 10.1523/JNEUROSCI.1871-20.2020 |
| Citation | Trudler D, et al. (2021) alpha-Synuclein Oligomers Induce Glutamate Release from Astrocytes and Excessive Extrasynaptic NMDAR Activity in Neurons, Thus Contributing to Synapse Loss. J Neurosci 41(10):2264-2273 |
| abstractText | 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 (alphaSyn), 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 alphaSyn and its mechanism of synaptic damage remain incompletely understood. Here, we show that alphaSyn oligomers induce Ca(2+)-dependent release of glutamate from astrocytes obtained from male and female mice, and that mice overexpressing alphaSyn 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 alphaSyn-overexpressing mice. Additionally, in patch-clamp recording from outside-out patches, we found that oligomerized alphaSyn can directly activate eNMDARs. In organotypic slices, oligomeric alphaSyn 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 alphaSyn, we find similar effects. Importantly, the improved NMDAR antagonist NitroSynapsin, which selectively inhibits extrasynaptic over physiological synaptic NMDAR activity, protects synapses from oligomeric alphaSyn-induced damage in our model systems, thus meriting further study for its therapeutic potential.SIGNIFICANCE STATEMENT Loss of synaptic function and ensuing neuronal loss are associated with disease progression in Parkinson's disease (PD), Lewy body dementia (LBD), and other neurodegenerative diseases. However, the mechanism of synaptic damage remains incompletely understood. alpha-Synuclein (alphaSyn) misfolds in PD/LBD, forming Lewy bodies and contributing to disease pathogenesis. Here, we found that misfolded/oligomeric alphaSyn releases excessive astrocytic glutamate, in turn activating neuronal extrasynaptic NMDA receptors (eNMDARs), thereby contributing to synaptic damage. Additionally, alphaSyn oligomers directly activate eNMDARs, further contributing to damage. While the FDA-approved drug memantine has been reported to offer some benefit in PD/LBD (Hershey and Coleman-Jackson, 2019), we find that the improved eNMDAR antagonist NitroSynapsin ameliorates alphaSyn-induced synaptic spine loss, providing potential disease-modifying intervention in PD/LBD. |
