Alpha-synuclein targets GluN2A NMDA receptor subunit causing striatal synaptic dysfunction and visuospatial memory alteration

Parkinson's disease is a progressive neurodegenerative disorder characterized by altered striatal dopaminergic signalling that leads to motor and cognitive deficits. Parkinson's disease is also characterized by abnormal presence of soluble toxic forms of α-synuclein that, when clustered in...

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Published in:Brain (London, England : 1878) Vol. 142; no. 5; p. 1365
Main Authors: Durante, Valentina, de Iure, Antonio, Loffredo, Vittorio, Vaikath, Nishant, De Risi, Maria, Paciotti, Silvia, Quiroga-Varela, Ana, Chiasserini, Davide, Mellone, Manuela, Mazzocchetti, Petra, Calabrese, Valeria, Campanelli, Federica, Mechelli, Alessandro, Di Filippo, Massimiliano, Ghiglieri, Veronica, Picconi, Barbara, El-Agnaf, Omar M, De Leonibus, Elvira, Gardoni, Fabrizio, Tozzi, Alessandro, Calabresi, Paolo
Format: Journal Article
Language:English
Published: England 01.05.2019
Subjects:
alpha-Synuclein - administration & dosage
alpha-Synuclein - toxicity
Animals
Corpus Striatum - drug effects
Corpus Striatum - metabolism
Corpus Striatum - pathology
Humans
Long-Term Potentiation - drug effects
Long-Term Potentiation - physiology
Male
Mice
Mice, Transgenic
Organ Culture Techniques
Protein Subunits - antagonists & inhibitors
Protein Subunits - metabolism
Rats
Rats, Wistar
Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors
Receptors, N-Methyl-D-Aspartate - metabolism
Spatial Memory - drug effects
Spatial Memory - physiology
Synapses - drug effects
Synapses - physiology
Visual Perception - drug effects
Visual Perception - physiology
dopamine
Parkinson’s disease
glutamate
long-term potentiation
monoclonal antibodies
ISSN:1460-2156, 1460-2156
Online Access:Get more information
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Summary:Parkinson's disease is a progressive neurodegenerative disorder characterized by altered striatal dopaminergic signalling that leads to motor and cognitive deficits. Parkinson's disease is also characterized by abnormal presence of soluble toxic forms of α-synuclein that, when clustered into Lewy bodies, represents one of the pathological hallmarks of the disease. However, α-synuclein oligomers might also directly affect synaptic transmission and plasticity in Parkinson's disease models. Accordingly, by combining electrophysiological, optogenetic, immunofluorescence, molecular and behavioural analyses, here we report that α-synuclein reduces N-methyl-d-aspartate (NMDA) receptor-mediated synaptic currents and impairs corticostriatal long-term potentiation of striatal spiny projection neurons, of both direct (D1-positive) and indirect (putative D2-positive) pathways. Intrastriatal injections of α-synuclein produce deficits in visuospatial learning associated with reduced function of GluN2A NMDA receptor subunit indicating that this protein selectively targets this subunit both in vitro and ex vivo. Interestingly, this effect is observed in spiny projection neurons activated by optical stimulation of either cortical or thalamic glutamatergic afferents. We also found that treatment of striatal slices with antibodies targeting α-synuclein prevents the α-synuclein-induced loss of long-term potentiation and the reduced synaptic localization of GluN2A NMDA receptor subunit suggesting that this strategy might counteract synaptic dysfunction occurring in Parkinson's disease.
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ISSN:1460-2156
1460-2156
DOI:10.1093/brain/awz065