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α-Synuclein propagation leads to synaptic abnormalities in the cortex through microglial synapse phagocytosis
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- Authors
- Issue Date
- 2023-10-17
- Publisher
- BMC
- Citation
- Molecular Brain, Vol.16(1):72
- Keywords
- Parkinson’s disease ; α-synuclein ; Protein aggregation ; Microglia ; Synapse degeneration
- Abstract
- The major neuropathologic feature of Parkinsons disease is the presence of widespread intracellular inclusions of α-synuclein known as Lewy bodies. Evidence suggests that these misfolded protein inclusions spread through the brain with disease progression. Changes in synaptic function precede neurodegeneration, and this extracellular α-synuclein can affect synaptic transmission. However, whether and how the spreading of α-synuclein aggregates modulates synaptic function before neuronal loss remains unknown. In the present study, we investigated the effect of intrastriatal injection of α-synuclein preformed fibrils (PFFs) on synaptic activity in the somatosensory cortex using a combination of whole-cell patch-clamp electrophysiology, histology, and Golgi-Cox staining. Intrastriatal PFF injection was followed by formation of phosphorylated α-synuclein inclusions in layer 5 of the somatosensory cortex, leading to a decrease in synapse density, dendritic spines, and spontaneous excitatory post-synaptic currents, without apparent neuronal loss. Additionally, three-dimensional reconstruction of microglia using confocal imaging showed an increase in the engulfment of synapses. Collectively, our data indicate that propagation of α-synuclein through neural networks causes abnormalities in synaptic structure and dynamics prior to neuronal loss.
- ISSN
- 1756-6606
- Language
- English
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