Skip to Content
MilliporeSigma
  • Dopamine-dependent early synaptic and motor dysfunctions induced by α-synuclein in the nigrostriatal circuit.

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

Brain : a journal of neurology (2021-07-24)
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, Paolo Calabresi
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 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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Goat Anti-Rat IgG Antibody, FITC conjugate, 26 mg/mL, Chemicon®
Sigma-Aldrich
Anti-Tyrosine Hydroxylase Antibody, clone LNC1, ascites fluid, clone LNC1, Chemicon®
Sigma-Aldrich
Anti-Dopamine Transporter Antibody, NT, clone DAT-Nt, culture supernatant, clone DAT-Nt, Chemicon®