α-Synuclein Oligomers Induce Glutamate Release from Astrocytes and Excessive Extrasynaptic NMDAR Activity in Neurons, Thus Contributing to Synapse Loss
| Autor: | Swagata Ghatak, Maria Talantova, Sara Sanz-Blasco, Mohd Waseem Akhtar, Jeffery W. Kelly, Stuart A. Lipton, William P. Lynch, Dorit Trudler, Juan C. Piña-Crespo, Karthik Bodhinathan, Yvonne S. Eisele |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male Induced Pluripotent Stem Cells Glutamic Acid Protein aggregation Hippocampal formation Hippocampus Receptors N-Methyl-D-Aspartate Synapse Rats Sprague-Dawley 03 medical and health sciences Mice 0302 clinical medicine medicine Animals Humans Cells Cultured Research Articles Neurons Lewy body Chemistry General Neuroscience Memantine Glutamate receptor Neurodegenerative Diseases medicine.disease Rats Mice Inbred C57BL 030104 developmental biology Astrocytes Synapses alpha-Synuclein NMDA receptor Female Neuroscience 030217 neurology & neurosurgery medicine.drug Frontotemporal dementia |
| Zdroj: | J Neurosci |
| ISSN: | 1529-2401 |
| Popis: | Synaptic and neuronal loss are major neuropathological characteristics of Parkinson's disease. Misfolded protein aggregates in the form of Lewy bodies, comprised mainly of α-synuclein (αSyn), 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 αSyn and its mechanism of synaptic damage remain incompletely understood. Here, we show that αSyn oligomers induce Ca2+-dependent release of glutamate from astrocytes obtained from male and female mice, and that mice overexpressing αSyn manifest increased tonic release of glutamatein vivo. In turn, this extracellular glutamate activates glutamate receptors, including extrasynaptic NMDARs (eNMDARs), on neurons both in culture and in hippocampal slices of αSyn-overexpressing mice. Additionally, in patch-clamp recording from outside-out patches, we found that oligomerized αSyn can directly activate eNMDARs. In organotypic slices, oligomeric αSyn 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 αSyn, we find similar effects. Importantly, the improved NMDAR antagonist NitroSynapsin, which selectively inhibits extrasynaptic over physiological synaptic NMDAR activity, protects synapses from oligomeric αSyn-induced damage in our model systems, thus meriting further study for its therapeutic potential.SIGNIFICANCE STATEMENTLoss 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. α-Synuclein (αSyn) misfolds in PD/LBD, forming Lewy bodies and contributing to disease pathogenesis. Here, we found that misfolded/oligomeric αSyn releases excessive astrocytic glutamate, in turn activating neuronal extrasynaptic NMDA receptors (eNMDARs), thereby contributing to synaptic damage. Additionally, αSyn 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 αSyn-induced synaptic spine loss, providing potential disease-modifying intervention in PD/LBD. |
| Databáze: | OpenAIRE |
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