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

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.