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

Tozzi, Alessandro; Iure, Antonio de; Bagetta, Vincenza; Tantucci, Michela; Durante, Valentina; Quiroga-Varela, Ana; Costa, Cinzia; Filippo, Massimiliano Di; Ghiglieri, Veronica; Latagliata, Emanuele Claudio; Węgrzynowicz, Michał; Decressac, Mickaël; Giampà, Carmela; Dalley, Jeffrey W.; Xia, Jing; Gardoni, Fabrizio; Mellone, Manuela; El-Agnaf, Omar M. A.; Ardah, Mustafa T.; Puglisi-Allegra, Stefano; Björklund, Anders; Spillantini, Maria Grazia; Picconi, Barbara; Calabresi, Paolo

doi:10.1016/j.biopsych.2015.08.013

Cited by 89 publications

(76 citation statements)

References 52 publications

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“…Extracellular α‐synuclein oligomers impair the expression of hippocampal LTP in normal rodents and increase basal synaptic transmission through an NMDA receptor‐dependent mechanism and an increase in the expression of GluR1‐containing AMPA receptors . Accordingly, acute in vitro application of human oligomers of α‐synuclein also mimicked the synaptic effects observed ex vivo in PD models …”

Section: Pathogenic Modelsmentioning

confidence: 93%

“…Overexpression of truncated or wild‐type human α‐synuclein caused a mild decrease in striatal DA levels. The selective loss of LTP in striatal ChIs was associated with learning deficits and motor alterations . These effects were dependent on direct interaction of α‐synuclein with the GluN2D‐expressing N ‐methyl‐ d ‐aspartic acid (NMDA) receptors in ChIs.…”

Section: Pathogenic Modelsmentioning

confidence: 99%

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Early synaptic dysfunction in Parkinson's disease: Insights from animal models

et al. 2016

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The appearance of motor manifestations in Parkinson's disease (PD) is invariably linked to degeneration of nigral dopaminergic neurons of the substantia nigra pars compacta. Traditional views on PD neuropathology have been grounded in the assumption that the prime event of neurodegeneration involves neuronal cell bodies with the accumulation of metabolic products. However, this view has recently been challenged by both clinical and experimental evidence. Neuropathological studies in human brain samples and both in vivo and in vitro models support the hypothesis that nigrostriatal synapses may indeed be affected at the earliest stages of the neurodegenerative process. The mechanisms leading to either structural or functional synaptic dysfunction are starting to be elucidated and include dysregulation of axonal transport, impairment of the exocytosis and endocytosis machinery, altered intracellular trafficking, and loss of corticostriatal synaptic plasticity. The aim of this review is to try to integrate different lines of evidence from both pathogenic and genetic animal models that, to different extents, suggest that early synaptic impairment may represent the key event in PD pathogenesis. Understanding the molecular and cellular events underlying such synaptopathy is a fundamental step toward developing specific biomarkers of early dopaminergic dysfunction and, more importantly, designing novel therapies targeting the synaptic apparatus of selective, vulnerable synapses. © 2016 International Parkinson and Movement Disorder Society.

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Section: Pathogenic Modelsmentioning

confidence: 93%

Section: Pathogenic Modelsmentioning

confidence: 99%

Early synaptic dysfunction in Parkinson's disease: Insights from animal models

et al. 2016

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“…8,[11][12][13][14] GluN2D is reduced in striatal cholinergic interneurons, and a switch between GluN2B and GluN2D occurs in projection neurons. [15][16][17] These studies suggest that neuronal adaptations that occur in the dopamine-depleted striatum involve a change in the subunit composition of NMDARs and an altered role of these receptors in NMDAR-dependent forms of synaptic plasticity.…”

Section: Introductionmentioning

confidence: 95%

CIQ, a positive allosteric modulator of GluN2C/D‐containing N‐methyl‐d‐aspartate receptors, rescues striatal synaptic plasticity deficit in a mouse model of Parkinson's disease

et al. 2017

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“…Prolonged exposure to α‐synOs affected NMDA‐ and AMPA‐mediated neuronal transmission and LTP in the hippocampus, driving an increase of glutamatergic synaptic transmission . Two experimental models of PD have shown that the cholinergic dysfunction induced by α‐synOs in the striatum is mediated by an interaction with the Gluamate N2 (GluN2) NMDA receptor subunit . An indirect effect on α‐synOs production involved different receptor types, including peroxisome proliferator‐activated receptor‐γ, adenosine A2A receptor, and the coactivator 1α …”

Section: α Synuclein Oligomersmentioning

confidence: 99%

Oligomeropathies and pathogenesis of Alzheimer and Parkinson's diseases

et al. 2016

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The term oligomeropathies defines the neurodegenerative disorders associated with protein misfolding, where small soluble aggregates (oligomers 4-200 KDa) are the cause of neuronal dysfunction and are responsible for spreading the pathology. The ability of these soluble β-sheet conformers to induce neuronal damage has been investigated in direct challenge with the monomeric and fibrillary structures, showing that only the oligomeric species affected the neurons. β amyloid oligomers were initially purified from Alzheimer brains and obtained using synthetic peptides. Together with the neuronal death, synaptic dysfunction, loss of spines, and LTP impairment were seen with the direct application of β amyloid oligomers. Similar results have been described with proteins associated with other neurodegenerative disorders. The biological activities of oligomeric forms of α synuclein have been described in Parkinson's disease and Lewy body dementia. Detrimental effects have been associated with the oligomeric forms of prion, tau, and huntingtin, the key proteins in prion diseases, frontotemporal dementia, and Huntington's disease, respectively. The molecular mechanisms of the oligomer-related toxic effects can be summarized under three headings: nonspecific perturbance of cellular and intracellular membranes, specific interaction with various cellular entities, and amyloid pore channel formation. To characterize and distinguish oligomer actions better, we compared the ability of β amyloid and α synuclein oligomers to induce cognitive impairment when applied directly into the brain in the same acute mouse model. We also investigated the role of inflammatory components. © 2016 International Parkinson and Movement Disorder Society.

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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

Cited by 89 publications

References 52 publications

Early synaptic dysfunction in Parkinson's disease: Insights from animal models

Early synaptic dysfunction in Parkinson's disease: Insights from animal models

CIQ, a positive allosteric modulator of GluN2C/D‐containing N‐methyl‐d‐aspartate receptors, rescues striatal synaptic plasticity deficit in a mouse model of Parkinson's disease

Oligomeropathies and pathogenesis of Alzheimer and Parkinson's diseases

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