Alpha-Synuclein Produces Early Behavioral Alterations Via Striatal Cholinergic Synaptic Dysfunction by Interacting with GluN2D N-Methyl-D-Aspartate Receptor Subunit

Alessandro Tozzi, Antonio de Iure, Vincenza Bagetta, Michela Tantucci, Valentina Durante, Ana Quiroga-Varela, Cinzia Costa, Massimiliano Di Filippo, Veronica Ghiglieri, Emanuele Claudio Latagliata, Michal Wegrzynowicz, Mickael Decressac, Carmela Giampà, Jeffrey W. Dalley, Jing Xia, Fabrizio Gardoni, Manuela Mellone, Omar Mukhtar El-Agnaf, Mustafa Taleb Ardah, Stefano Puglisi-AllegraAnders Björklund, Maria Grazia Spillantini, Barbara Picconi, Paolo Calabresi

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Advanced Parkinson's disease (PD) is characterized by massive degeneration of nigral dopaminergic neurons, dramatic motor and cognitive alterations, and presence of nigral Lewy bodies, whose main constituent is α-synuclein (α-syn). However, the synaptic mechanisms underlying behavioral and motor effects induced by early selective overexpression of nigral α-syn are still a matter of debate. Methods: We performed behavioral, molecular, and immunohistochemical analyses in two transgenic models of PD, mice transgenic for truncated human α-synuclein 1-120 and rats injected with the adeno-associated viral vector carrying wild-type human α-synuclein. We also investigated striatal synaptic plasticity by electrophysiological recordings from spiny projection neurons and cholinergic interneurons. Results: We found that overexpression of truncated or wild-type human α-syn causes partial reduction of striatal dopamine levels and selectively blocks the induction of long-term potentiation in striatal cholinergic interneurons, producing early memory and motor alterations. These effects were dependent on α-syn modulation of the GluN2D-expressing N-methyl-D-aspartate receptors in cholinergic interneurons. Acute in vitro application of human α-syn oligomers mimicked the synaptic effects observed ex vivo in PD models. Conclusions: We suggest that striatal cholinergic dysfunction, induced by a direct interaction between α-syn and GluN2D-expressing N-methyl-D-aspartate receptors, represents a precocious biological marker of the disease.

Original languageEnglish
JournalBiological Psychiatry
DOIs
Publication statusAccepted/In press - May 5 2015

Keywords

  • Animal models
  • Cholinergic interneurons
  • Dopamine
  • Long-term potentiation
  • Parkinson's disease
  • Striatum

ASJC Scopus subject areas

  • Biological Psychiatry

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