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

  • Alessandro Tozzi
    Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy
  • Miriam Sciaccaluga
    Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy
  • Vittorio Loffredo
    Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy
  • Alfredo Megaro
    Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy
  • Ada Ledonne
    Laboratory of Experimental Neuroscience, Santa Lucia Foundation IRCCS, 00143 Rome, Italy
  • Antonella Cardinale
    Department of Experimental Neurophysiology, IRCCS San Raffaele, 00166 Rome, Italy
  • Mauro Federici
    Laboratory of Experimental Neuroscience, Santa Lucia Foundation IRCCS, 00143 Rome, Italy
  • Laura Bellingacci
    Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy
  • Silvia Paciotti
    Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy
  • Elena Ferrari
    Department of Pharmacological and Biomolecular Sciences, University of Milan, 20133 Milan, Italy
  • Antonino La Rocca
    Institute of Biochemistry and Cell Biology - IBBC, CNR, 00015 Monterotondo scalo, Italy
  • Alessandro Martini
    Laboratory of Experimental Neuroscience, Santa Lucia Foundation IRCCS, 00143 Rome, Italy
  • Nicola B Mercuri
    Laboratory of Experimental Neuroscience, Santa Lucia Foundation IRCCS, 00143 Rome, Italy
  • Fabrizio Gardoni
    Department of Pharmacological and Biomolecular Sciences, University of Milan, 20133 Milan, Italy
  • Barbara Picconi
    Department of Experimental Neurophysiology, IRCCS San Raffaele, 00166 Rome, Italy
  • Veronica Ghiglieri
    San Raffaele University, 00166 Rome, Italy
  • Elvira De Leonibus
    Institute of Biochemistry and Cell Biology - IBBC, CNR, 00015 Monterotondo scalo, Italy
  • Paolo Calabresi
    Neurological Clinic, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy

抄録

<jats:title>Abstract</jats:title> <jats:p>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 extracellular release of α-synuclein aggregates, as well as with their spread 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, we 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 behavioural alterations. We found that intrastriatal α-synuclein-preformed fibrils perturb the firing rate of dopaminergic neurons in 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 subchronic 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.</jats:p>

収録刊行物

  • Brain

    Brain 144 (11), 3477-3491, 2021-07-23

    Oxford University Press (OUP)

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