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

Valentina Durante, Antonio de Iure, Vittorio Loffredo, Nishant Vaikath, Maria De Risi, Silvia Paciotti, Ana Quiroga-Varela, Davide Chiasserini, Manuela Mellone, Petra Mazzocchetti, Valeria Calabrese, Federica Campanelli, Alessandro Mechelli, Massimiliano Di Filippo, Veronica Ghiglieri, Barbara Picconi, Omar M. El-Agnaf, Elvira De Leonibus, Fabrizio Gardoni, Alessandro TozziPaolo Calabresi

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)1365-1385
Number of pages21
JournalBrain : a journal of neurology
Volume142
Issue number5
DOIs
Publication statusPublished - May 1 2019

Fingerprint

Synucleins
Corpus Striatum
alpha-Synuclein
Parkinson Disease
Long-Term Potentiation
Optogenetics
Lewy Bodies
Neurons
Neuronal Plasticity
Poisons
Protein Subunits
Synaptic Transmission
Neurodegenerative Diseases
Fluorescent Antibody Technique
aspartic acid receptor
Learning
Injections
Antibodies

Keywords

  • dopamine
  • glutamate
  • long-term potentiation
  • monoclonal antibodies
  • Parkinson’s disease

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

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

In: Brain : a journal of neurology, Vol. 142, No. 5, 01.05.2019, p. 1365-1385.

Research output: Contribution to journalArticle

Durante, V, de Iure, A, Loffredo, V, Vaikath, N, De Risi, M, Paciotti, S, Quiroga-Varela, A, Chiasserini, D, Mellone, M, Mazzocchetti, P, Calabrese, V, Campanelli, F, Mechelli, A, Di Filippo, M, Ghiglieri, V, Picconi, B, El-Agnaf, OM, De Leonibus, E, Gardoni, F, Tozzi, A & Calabresi, P 2019, 'Alpha-synuclein targets GluN2A NMDA receptor subunit causing striatal synaptic dysfunction and visuospatial memory alteration', Brain : a journal of neurology, vol. 142, no. 5, pp. 1365-1385. https://doi.org/10.1093/brain/awz065
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. / Alpha-synuclein targets GluN2A NMDA receptor subunit causing striatal synaptic dysfunction and visuospatial memory alteration. In: Brain : a journal of neurology. 2019 ; Vol. 142, No. 5. pp. 1365-1385.
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AU - Vaikath, Nishant

AU - De Risi, Maria

AU - Paciotti, Silvia

AU - Quiroga-Varela, Ana

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AU - Mazzocchetti, Petra

AU - Calabrese, Valeria

AU - Campanelli, Federica

AU - Mechelli, Alessandro

AU - Di Filippo, Massimiliano

AU - Ghiglieri, Veronica

AU - Picconi, Barbara

AU - El-Agnaf, Omar M.

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AU - Gardoni, Fabrizio

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AU - Calabresi, Paolo

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N2 - 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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