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

Paolo Calabresi, 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 GardoniAlessandro Tozzi

Risultato della ricerca: Contributo in rivistaArticolo in rivista

16 Citazioni (Scopus)

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.
Lingua originaleEnglish
pagine (da-a)1365-1385
Numero di pagine21
RivistaBRAIN
Volume142
DOI
Stato di pubblicazionePubblicato - 2019

Keywords

  • Animals
  • Corpus Striatum
  • Humans
  • Long-Term Potentiation
  • Male
  • Mice
  • Mice, Transgenic
  • Organ Culture Techniques
  • Parkinson's disease
  • Protein Subunits
  • Rats
  • Rats, Wistar
  • Receptors, N-Methyl-D-Aspartate
  • Spatial Memory
  • Synapses
  • Visual Perception
  • alpha-Synuclein
  • dopamine
  • glutamate
  • long-term potentiation
  • monoclonal antibodies

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