期刊
BIOLOGICAL PSYCHIATRY
卷 79, 期 5, 页码 402-414出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.biopsych.2015.08.013
关键词
Animal models; Cholinergic interneurons; Dopamine; Long-term potentiation; Parkinson's disease; Striatum
资金
- European Community [222918]
- Progetto di Ricerca di Interesse Nazionale [2010AHHP5H]
- Progetti del Ministero della Salute
- Giovani Ricercatori [GR-2008-1142336, GR-2010-2315007]
- Ricerca Finalizzata [RF-2011-02349806, RF-2013-02356215]
- Fondazione con il Sud [2011- PDR-13]
- Fondazione Cassa di Risparmio di Perugia
- Fondazione Cariplo [2014-0660]
- Parkinson's UK
- Bayer Schering
- Biogen
- Boehringer Ingelheim
- Eisai
- Lundbeck
- Merck Sharp Dohme
- Novartis
- Sanofi-Aventis
- Sigma Tau
- UCB
- Fondazione Santa Lucia Institutes for Research, Hospitalization and Health Care, Ministero della Salute
- Parkinson's UK [G-1102] Funding Source: researchfish
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.
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