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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.

journal_name

Biol Psychiatry

journal_title

Biological psychiatry

authors

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,El-Agnaf OM,Ardah MT,Puglisi-A

doi

10.1016/j.biopsych.2015.08.013

subject

Has Abstract

pub_date

2016-03-01 00:00:00

pages

402-414

issue

eissn

0006-3223

issn

1873-2402

pii

S0006-3223(15)00678-2

journal_volume

pub_type

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