NMDA receptors are altered in the substantia nigra pars reticulata and their blockade ameliorates motor deficits in experimental parkinsonism.
Animals
Excitatory Amino Acid Antagonists
/ pharmacology
Male
Mice
Mice, Inbred C57BL
Motor Disorders
/ chemically induced
Oxidopamine
/ toxicity
Parkinsonian Disorders
/ chemically induced
Pars Reticulata
/ drug effects
Receptors, N-Methyl-D-Aspartate
/ antagonists & inhibitors
Substantia Nigra
/ drug effects
Synaptic Transmission
/ drug effects
Basal ganglia
GluN2 subunits
NMDA receptors
Parkinson's disease
Substantia nigra reticulata
Synaptic transmission
Journal
Neuropharmacology
ISSN: 1873-7064
Titre abrégé: Neuropharmacology
Pays: England
ID NLM: 0236217
Informations de publication
Date de publication:
01 09 2020
01 09 2020
Historique:
received:
16
12
2019
revised:
06
04
2020
accepted:
11
05
2020
pubmed:
1
6
2020
medline:
8
7
2021
entrez:
1
6
2020
Statut:
ppublish
Résumé
In Parkinson's disease (PD) reduced levels of dopamine (DA) in the striatum lead to an abnormal circuit activity of the basal ganglia and an increased output through the substantia nigra pars reticulata (SNr) and the globus pallidus internal part. Synaptic inputs to the SNr shape its activity, however, the properties of glutamatergic synaptic transmission in this output nucleus of the basal ganglia in control and DA-depleted conditions are not fully elucidated. Using whole-cell patch-clamp recordings and pharmacological tools, we examined alterations in glutamatergic synaptic transmission in the SNr of a mouse model of PD, i.e. mice with unilateral 6-OHDA lesion of DA neurons in the substantia nigra pars compacta, as compared to control mice. We found that AMPA receptor (AMPAR)-mediated spontaneous and evoked excitatory postsynaptic currents (sEPSCs and eEPSCs) were not altered. The AMPA/NMDA ratio was significantly decreased in 6-OHDA-lesioned mice, suggesting an increased synaptic function of NMDA receptors (NMDARs) in DA-depleted mice. The decay kinetics of NMDAR-eEPSCs were faster in 6-OHDA-lesioned mice, indicating a possible change in the subunit composition of synaptic NMDARs. In control mice NMDAR-eEPSCs were mediated by diheteromeric NMDARs made of GluN2A, GluN2B and GluN2D. In 6-OHDA-lesioned mice the function of diheteromeric NMDARs containing either GluN2B or GluN2D was dramatically decreased, whereas the function of diheteromeric NMDARs made of GluN2A was preserved. Microinjections of an NMDAR antagonist into the SNr of 6-OHDA-lesioned mice resulted in significant improvements in spontaneous locomotion. This study identifies novel alterations occurring at excitatory synapses in the basal ganglia output nucleus following DA depletion. An increased synaptic NMDAR function, due to an altered subunit composition, might contribute to hyperactivation of SNr neurons in the DA depleted state and to motor impairments in PD.
Identifiants
pubmed: 32474027
pii: S0028-3908(20)30204-5
doi: 10.1016/j.neuropharm.2020.108136
pii:
doi:
Substances chimiques
Excitatory Amino Acid Antagonists
0
Receptors, N-Methyl-D-Aspartate
0
Oxidopamine
8HW4YBZ748
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
108136Informations de copyright
Copyright © 2020 Elsevier Ltd. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of competing interest The authors declare no conflicts of interest.