title: Alpha-Synuclein Produces Early Behavioral Alterations via Striatal Cholinergic Synaptic Dysfunction by Interacting With GluN2D N-Methyl-D-Aspartate Receptor Subunit.
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.
authors.affiliation: Department of Experimental Medicine, University of Perugia, Perugia; Fondazione Santa Lucia, Institutes for Research, Hospitalization and Health Care, Rome.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Tozzi
authors.affiliation: Department of Medicine, Hospital Santa Maria della Misericordia, Neurological Clinic, University of Perugia, Perugia.
authors.forename: Antonio
authors.initials: A
authors.lastname: de Iure
authors.affiliation: Fondazione Santa Lucia, Institutes for Research, Hospitalization and Health Care, Rome.
authors.forename: Vincenza
authors.initials: V
authors.lastname: Bagetta
authors.affiliation: Department of Medicine, Hospital Santa Maria della Misericordia, Neurological Clinic, University of Perugia, Perugia.
authors.forename: Michela
authors.initials: M
authors.lastname: Tantucci
authors.affiliation: Department of Medicine, Hospital Santa Maria della Misericordia, Neurological Clinic, University of Perugia, Perugia.
authors.forename: Valentina
authors.initials: V
authors.lastname: Durante
authors.affiliation: Department of Medicine, Hospital Santa Maria della Misericordia, Neurological Clinic, University of Perugia, Perugia.
authors.forename: Ana
authors.initials: A
authors.lastname: Quiroga-Varela
authors.affiliation: Department of Medicine, Hospital Santa Maria della Misericordia, Neurological Clinic, University of Perugia, Perugia.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Costa
authors.affiliation: Department of Medicine, Hospital Santa Maria della Misericordia, Neurological Clinic, University of Perugia, Perugia.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Di Filippo
authors.affiliation: Fondazione Santa Lucia, Institutes for Research, Hospitalization and Health Care, Rome; Department of Philosophy, Human, Social, and Educational Sciences, University of Perugia, Perugia.
authors.forename: Veronica
authors.initials: V
authors.lastname: Ghiglieri
authors.affiliation: Fondazione Santa Lucia, Institutes for Research, Hospitalization and Health Care, Rome; Department of Psychology, "Daniel Bovet" Centre, University of Rome "La Sapienza", Rome, Italy.
authors.forename: Emanuele Claudio
authors.initials: EC
authors.lastname: Latagliata
authors.affiliation: Department of Clinical Neurosciences, Cambridge Centre for Brain Repair, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Michal
authors.initials: M
authors.lastname: Wegrzynowicz
authors.affiliation: Department of Experimental Medical Sciences, Wallenberg Neuroscience Center, Lund University, Lund, Sweden.
authors.forename: Mickael
authors.initials: M
authors.lastname: Decressac
authors.affiliation: Fondazione Santa Lucia, Institutes for Research, Hospitalization and Health Care, Rome.
authors.forename: Carmela
authors.initials: C
authors.lastname: Giampà
authors.affiliation: Department of Psychology and Department of Psychiatry, Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Dalley
authors.affiliation: Department of Psychology and Department of Psychiatry, Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Jing
authors.initials: J
authors.lastname: Xia
authors.affiliation: Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Gardoni
authors.affiliation: Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Mellone
authors.affiliation: Department of Biochemistry, Faculty of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates.
authors.forename: Omar Mukhtar
authors.initials: OM
authors.lastname: El-Agnaf
authors.affiliation: Department of Biochemistry, Faculty of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates.
authors.forename: Mustafa Taleb
authors.initials: MT
authors.lastname: Ardah
authors.affiliation: Fondazione Santa Lucia, Institutes for Research, Hospitalization and Health Care, Rome; Department of Psychology, "Daniel Bovet" Centre, University of Rome "La Sapienza", Rome, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Puglisi-Allegra
authors.affiliation: Department of Experimental Medical Sciences, Wallenberg Neuroscience Center, Lund University, Lund, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Björklund
authors.affiliation: Department of Clinical Neurosciences, Cambridge Centre for Brain Repair, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Spillantini
authors.affiliation: Fondazione Santa Lucia, Institutes for Research, Hospitalization and Health Care, Rome.
authors.forename: Barbara
authors.initials: B
authors.lastname: Picconi
authors.affiliation: Fondazione Santa Lucia, Institutes for Research, Hospitalization and Health Care, Rome; Department of Medicine, Hospital Santa Maria della Misericordia, Neurological Clinic, University of Perugia, Perugia. Electronic address: paolo.calabresi@unipg.it.
authors.forename: Paolo
authors.initials: P
authors.lastname: Calabresi
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D059329:Cholinergic Neurons / Q000187:drug effects*; D000229:Dependovirus; D004195:Disease Models, Animal; D004298:Dopamine / Q000502:physiology*; D005260:Female; D006801:Humans; D017774:Long-Term Potentiation; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D017072:Neostriatum / Q000502:physiology; D010300:Parkinson Disease / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics*; D011994:Recombinant Proteins / Q000235:genetics; D009435:Synaptic Transmission; D051844:alpha-Synuclein / Q000235:genetics*
chemical_list: C464436:NR2D NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D011994:Recombinant Proteins; C497604:SNCA protein, human; D051844:alpha-Synuclein; D004298:Dopamine
keywords: Animal models; Cholinergic interneurons; Dopamine; Long-term potentiation; Parkinson’s disease; Striatum