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

Biol Psychiatry. 2016 Mar 1;79(5):402-414. doi: 10.1016/j.biopsych.2015.08.013. Epub 2015 Aug 20.


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.

Keywords: Animal models; Cholinergic interneurons; Dopamine; Long-term potentiation; Parkinson’s disease; Striatum.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Cholinergic Neurons / drug effects*
  • Dependovirus
  • Disease Models, Animal
  • Dopamine / physiology*
  • Female
  • Humans
  • Long-Term Potentiation
  • Male
  • Mice
  • Mice, Transgenic
  • Neostriatum / physiology
  • Parkinson Disease / drug therapy*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, N-Methyl-D-Aspartate / genetics*
  • Recombinant Proteins / genetics
  • Synaptic Transmission
  • alpha-Synuclein / genetics*


  • NR2D NMDA receptor
  • Receptors, N-Methyl-D-Aspartate
  • Recombinant Proteins
  • SNCA protein, human
  • alpha-Synuclein
  • Dopamine