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 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.

Tozzi, A., De Iure, A., Bagetta, V., Tantucci, M., Durante, V., Quiroga Varela, A., Costa, C., Di Filippo, M., Ghiglieri, V., Latagliata, E. C., Wegrzynowicz, M., Decressac, M., Giampa', C., Dalley, J. W., Xia, J., Gardoni, F., Mellone, M., El Agnaf, O. M., Ardah, M. T., Puglisi Allegra, S., Björklund, A., Spillantini, M. G., Picconi, B., Calabresi, P., Alpha-Synuclein Produces Early Behavioral Alterations via Striatal Cholinergic Synaptic Dysfunction by Interacting With GluN2D N-Methyl-D-Aspartate Receptor Subunit, <<BIOLOGICAL PSYCHIATRY>>, 2016; 79 (5): 402-414. [doi:10.1016/j.biopsych.2015.08.013] [http://hdl.handle.net/10807/95566]

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

Giampa', Carmela;Calabresi, Paolo
2016

Abstract

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 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.
2016
Inglese
Tozzi, A., De Iure, A., Bagetta, V., Tantucci, M., Durante, V., Quiroga Varela, A., Costa, C., Di Filippo, M., Ghiglieri, V., Latagliata, E. C., Wegrzynowicz, M., Decressac, M., Giampa', C., Dalley, J. W., Xia, J., Gardoni, F., Mellone, M., El Agnaf, O. M., Ardah, M. T., Puglisi Allegra, S., Björklund, A., Spillantini, M. G., Picconi, B., Calabresi, P., Alpha-Synuclein Produces Early Behavioral Alterations via Striatal Cholinergic Synaptic Dysfunction by Interacting With GluN2D N-Methyl-D-Aspartate Receptor Subunit, <<BIOLOGICAL PSYCHIATRY>>, 2016; 79 (5): 402-414. [doi:10.1016/j.biopsych.2015.08.013] [http://hdl.handle.net/10807/95566]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10807/95566
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