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

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• 作者：Alessandro Tozzi^a ; ^b ; Antonio de Iure^c ; Vincenza Bagetta^b ; Michela Tantucci^c ; Valentina Durante^c ; Ana Quiroga-Varela^c ; Cinzia Costa^c ; Massimiliano Di Filippo^c ; Veronica Ghiglieri^b ; ^d ; Emanuele Claudio Latagliata^b ; ^e ; Michal Wegrzynowicz^f ; Mickael Decressac^g ; Carmela Giampà ; ^b ; Jeffrey W. Dalley^h ; Jing Xia^h ; Fabrizio Gardoniⁱ ; Manuela Melloneⁱ ; Omar Mukhtar El-Agnaf^j ; Mustafa Taleb Ardah^j ; Stefano Puglisi-Allegra^b ; ^e ; Anders Bjö ; rklund^g ; Maria Grazia Spillantini^f ; Barbara Picconi^b ; Paolo Calabresi^b ; ^c ; ^{paolo.calabresi@unipg.it" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Animal models ; Cholinergic interneurons ; Dopamine ; Long-term potentiation ; Parkinson&rsquo ; s disease ; Striatum
• 刊名：Biological Psychiatry
• 出版年：2016
• 出版时间：1 March 2016
• 年：2016
• 卷：79
• 期：5
• 页码：402-414
• 全文大小：6116 K

文摘

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.