Dopamine-dependent early synaptic and motor dysfunctions induced by α-synuclein in the nigrostriatal circuit.
Parkinson’s disease
long-term depression
long-term potentiation
substantia nigra
synaptic plasticity
Journal
Brain : a journal of neurology
ISSN: 1460-2156
Titre abrégé: Brain
Pays: England
ID NLM: 0372537
Informations de publication
Date de publication:
16 12 2021
16 12 2021
Historique:
received:
02
01
2021
revised:
26
05
2021
accepted:
14
06
2021
pubmed:
24
7
2021
medline:
19
2
2022
entrez:
23
7
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34297092
pii: 6326771
doi: 10.1093/brain/awab242
pmc: PMC8677552
doi:
Substances chimiques
alpha-Synuclein
0
Dopamine
VTD58H1Z2X
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3477-3491Subventions
Organisme : NINDS NIH HHS
ID : R01 NS045962
Pays : United States
Organisme : NINDS NIH HHS
ID : R56 NS045962
Pays : United States
Informations de copyright
© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.
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