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 Ali El-Agnaf, Mustafa Taleb Ardah, Stefano Puglisi-Allegra & 4 others Anders Björklund, Maria Grazia Spillantini, Barbara Picconi, Paolo Calabresi

Research output: Contribution to journalArticle

24 Citations (Scopus)

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
Pages (from-to)402-414
Number of pages13
JournalBiological Psychiatry
Volume79
Issue number5
DOIs
Publication statusPublished - 1 Mar 2016
Externally publishedYes

Fingerprint

Corpus Striatum
alpha-Synuclein
N-Methyl-D-Aspartate Receptors
Cholinergic Agents
Interneurons
Substantia Nigra
Synucleins
Parkinson Disease
Lewy Bodies
Neuronal Plasticity
Cholinergic Neurons
Long-Term Potentiation
Dopaminergic Neurons
Transgenic Mice
Dopamine
Biomarkers

Keywords

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

ASJC Scopus subject areas

  • Biological Psychiatry

Cite this

Alpha-Synuclein Produces Early Behavioral Alterations via Striatal Cholinergic Synaptic Dysfunction by Interacting With GluN2D N-Methyl-D-Aspartate Receptor Subunit. / Tozzi, Alessandro; de Iure, Antonio; Bagetta, Vincenza; Tantucci, Michela; Durante, Valentina; Quiroga-Varela, Ana; Costa, Cinzia; Di Filippo, Massimiliano; Ghiglieri, Veronica; Latagliata, Emanuele Claudio; Wegrzynowicz, Michal; Decressac, Mickael; Giampà, Carmela; Dalley, Jeffrey W.; Xia, Jing; Gardoni, Fabrizio; Mellone, Manuela; Ali El-Agnaf, Omar; Ardah, Mustafa Taleb; Puglisi-Allegra, Stefano; Björklund, Anders; Spillantini, Maria Grazia; Picconi, Barbara; Calabresi, Paolo.

In: Biological Psychiatry, Vol. 79, No. 5, 01.03.2016, p. 402-414.

Research output: Contribution to journalArticle

Tozzi, A, de Iure, A, Bagetta, V, Tantucci, M, Durante, V, Quiroga-Varela, A, Costa, C, Di Filippo, M, Ghiglieri, V, Latagliata, EC, Wegrzynowicz, M, Decressac, M, Giampà, C, Dalley, JW, Xia, J, Gardoni, F, Mellone, M, Ali El-Agnaf, O, Ardah, MT, Puglisi-Allegra, S, Björklund, A, Spillantini, MG, Picconi, B & Calabresi, P 2016, 'Alpha-Synuclein Produces Early Behavioral Alterations via Striatal Cholinergic Synaptic Dysfunction by Interacting With GluN2D N-Methyl-D-Aspartate Receptor Subunit', Biological Psychiatry, vol. 79, no. 5, pp. 402-414. https://doi.org/10.1016/j.biopsych.2015.08.013
Tozzi, Alessandro ; de Iure, Antonio ; Bagetta, Vincenza ; Tantucci, Michela ; Durante, Valentina ; Quiroga-Varela, Ana ; Costa, Cinzia ; Di Filippo, Massimiliano ; Ghiglieri, Veronica ; Latagliata, Emanuele Claudio ; Wegrzynowicz, Michal ; Decressac, Mickael ; Giampà, Carmela ; Dalley, Jeffrey W. ; Xia, Jing ; Gardoni, Fabrizio ; Mellone, Manuela ; Ali El-Agnaf, Omar ; Ardah, Mustafa Taleb ; Puglisi-Allegra, Stefano ; Björklund, Anders ; Spillantini, Maria Grazia ; Picconi, Barbara ; Calabresi, Paolo. / Alpha-Synuclein Produces Early Behavioral Alterations via Striatal Cholinergic Synaptic Dysfunction by Interacting With GluN2D N-Methyl-D-Aspartate Receptor Subunit. In: Biological Psychiatry. 2016 ; Vol. 79, No. 5. pp. 402-414.
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T1 - Alpha-Synuclein Produces Early Behavioral Alterations via Striatal Cholinergic Synaptic Dysfunction by Interacting With GluN2D N-Methyl-D-Aspartate Receptor Subunit

AU - Tozzi, Alessandro

AU - de Iure, Antonio

AU - Bagetta, Vincenza

AU - Tantucci, Michela

AU - Durante, Valentina

AU - Quiroga-Varela, Ana

AU - Costa, Cinzia

AU - Di Filippo, Massimiliano

AU - Ghiglieri, Veronica

AU - Latagliata, Emanuele Claudio

AU - Wegrzynowicz, Michal

AU - Decressac, Mickael

AU - Giampà, Carmela

AU - Dalley, Jeffrey W.

AU - Xia, Jing

AU - Gardoni, Fabrizio

AU - Mellone, Manuela

AU - Ali El-Agnaf, Omar

AU - Ardah, Mustafa Taleb

AU - Puglisi-Allegra, Stefano

AU - Björklund, Anders

AU - Spillantini, Maria Grazia

AU - Picconi, Barbara

AU - Calabresi, Paolo

PY - 2016/3/1

Y1 - 2016/3/1

N2 - 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.

AB - 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.

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KW - Cholinergic interneurons

KW - Dopamine

KW - Long-term potentiation

KW - Parkinson's disease

KW - Striatum

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