Dopamine-dependent early synaptic and motor dysfunctions induced by α-synuclein in the nigrostriatal circuit

Paolo Calabresi, Alessandro Tozzi, Miriam Sciaccaluga, Vittorio Loffredo, Alfredo Megaro, Ada Ledonne, Antonella Cardinale, Mauro Federici, Laura Bellingacci, Silvia Paciotti, Elena Ferrari, Antonino La Rocca, Alessandro Martini, Nicola B Mercuri, Fabrizio Gardoni, Barbara Picconi, Veronica Ghiglieri, Elvira De Leonibus

Research output: Contribution to journalArticle

Abstract

Misfolding and aggregation of α-synuclein are specific features of Parkinson's disease and other neurodegenerative diseases defined as synucleinopathies. Parkinson's disease progression has been correlated with the formation and the extracellular release of α-synuclein aggregates, as well as with their spreading from neuron to neuron. Therapeutic interventions in the initial stages of Parkinson's disease require a clear understanding of the mechanisms by which α-synuclein disrupts the physiological synaptic and plastic activity of the basal ganglia. For this reason, here we have identified two early time points to clarify how the intrastriatal injection of α-synuclein preformed fibrils in rodents, via retrograde transmission, induces time-dependent electrophysiological and behavioral alterations. We found that intrastriatal α-synuclein preformed fibrils perturb the firing rate of dopaminergic neurons of the substantia nigra pars compacta while the discharge of putative GABAergic cells of the substantia nigra pars reticulata is unchanged. The α-synuclein-induced dysregulation of nigrostriatal function also impairs, in a time-dependent manner, the two main forms of striatal synaptic plasticity, long-term potentiation and long-term depression. We also observed an increased glutamatergic transmission measured as an augmented frequency of spontaneous excitatory synaptic currents. These changes in neuronal function in the substantia nigra pars compacta and striatum were observed before overt neuronal death occurred. In an additional set of experiments, we were able to rescue α-synuclein-induced alterations of motor function, striatal synaptic plasticity, and increased spontaneous excitatory synaptic currents by a sub-chronic treatment with L-Dopa, a precursor of dopamine widely used in the therapy of Parkinson's disease, clearly demonstrating that a dysfunctional dopamine system plays a critical role in the early phases of the disease.
Original languageEnglish
Pages (from-to)N/A-N/A
JournalBRAIN
Volume23
DOIs
Publication statusPublished - 2021

Keywords

  • Parkinson’s disease
  • long-term depression (LTD)
  • synaptic plasticity
  • substantia nigra
  • long-term potentiation (LTP)

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