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

被引：82

作者：

Tozzi, Alessandro ^{[1
,2
]}

de Iure, Antonio ^{[3
]}

Bagetta, Vincenza ^{[2
]}

Tantucci, Michela ^{[3
]}

Durante, Valentina ^{[3
]}

Quiroga-Varela, Ana ^{[3
]}

Costa, Cinzia ^{[3
]}

Di Filippo, Massimiliano ^{[3
]}

Ghiglieri, Veronica ^{[2
,4
]}

Latagliata, Emanuele Claudio ^{[2
,5
]}

Wegrzynowicz, Michal ^{[6
]}

Decressac, Mickael ^{[7
]}

Giampa, Carmela ^{[2
]}

Dalley, Jeffrey W. ^{[8
,9
]}

Xia, Jing ^{[8
,9
]}

Gardoni, Fabrizio ^{[10
]}

Mellone, Manuela ^{[10
]}

El-Agnaf, Omar Mukhtar ^{[11
]}

Ardah, Mustafa Taleb ^{[11
]}

Puglisi-Allegra, Stefano ^{[2
,5
]}

Bjorklund, Anders ^{[6
,7
]}

Spillantini, Maria Grazia

Picconi, Barbara ^{[2
]}

Calabresi, Paolo ^{[2
,3
]}

机构：

[1] Univ Perugia, Dept Expt Med, I-06100 Perugia, Italy

[2] Fdn Santa Lucia, Sci Inst Res Hospitalizat & Hlth Care, Rome, Italy

[3] Univ Perugia, Neurol Clin, Hosp Santa Maria della Misericordia, Dept Med, I-06100 Perugia, Italy

[4] Univ Perugia, Dept Philosophy, Human Social & Educ Sci, I-06100 Perugia, Italy

[5] Univ Roma La Sapienza, Dept Psychol, Daniel Bovet Ctr, Piazzale Aldo Moro 5, I-00185 Rome, Italy

[6] Univ Cambridge, Cambridge Ctr Brain Repair, Dept Clin Neurosci, Cambridge, England

[7] Lund Univ, Wallenberg Neurosci Ctr, Dept Expt Med Sci, Lund, Sweden

[8] Univ Cambridge, Dept Psychol, Cambridge, England

[9] Univ Cambridge, Dept Psychiat, Behav & Clin Neurosci Inst, Cambridge, England

[10] Univ Milan, Dept Pharmacol & Biomol Sci, Milan, Italy

[11] United Arab Emirates Univ, Fac Med & Hlth Sci, Dept Biochem, Al Ain, U Arab Emirates

来源：

BIOLOGICAL PSYCHIATRY | 2016年 / 79卷 / 05期

关键词：

Animal models; Cholinergic interneurons; Dopamine; Long-term potentiation; Parkinson's disease; Striatum; MEDIUM SPINY NEURONS; PARKINSONS-DISEASE; NMDA-RECEPTOR; DOPAMINE RELEASE; MOUSE MODEL; ALLOSTERIC MODULATION; INDIRECT PATHWAYS; BASAL GANGLIA; RAT STRIATUM; INTERNEURONS;

D O I：

10.1016/j.biopsych.2015.08.013

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

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 alpha-synuclein (alpha-syn). However, the synaptic mechanisms underlying behavioral and motor effects induced by early selective overexpression of nigral alpha-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 alpha-synuclein 1-120 and rats injected with the adeno-associated viral vector carrying wild-type human alpha-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 alpha-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 alpha-syn modulation of the GluN2D-expressing N-methyl-D-aspartate receptors in cholinergic interneurons. Acute in vitro application of human alpha-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 a-syn and GluN2D-expressing N-methyl-D-aspartate receptors, represents a precocious biological marker of the disease.

引用

页码：402 / 414

页数：13

共 53 条

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