α-Synuclein Aggregates Increase the Conductance of Substantia Nigra Dopamine Neurons, an Effect Partly Reversed by the KATP Channel Inhibitor Glibenclamide.
eNeuro
; 8(1)2021.
Article
in En
| MEDLINE
| ID: mdl-33229413
ABSTRACT
Dopaminergic neurons (DNs) in the substantia nigra pars compacta (SNpc) form an important part of the basal ganglia circuitry, playing key roles in movement initiation and coordination. A hallmark of Parkinson's disease (PD) is the degeneration of these SNpc DNs leading to akinesia, bradykinesia and tremor. There is gathering evidence that oligomeric α-synuclein (α-syn) is one of the major pathologic species in PD, with its deposition in Lewy bodies (LBs) closely correlated with disease progression. However, the precise mechanisms underlying the effects of oligomeric α-syn on DN function have yet to be fully defined. Here, we have combined electrophysiological recording and detailed analysis to characterize the time-dependent effects of α-syn aggregates (consisting of oligomers and possibly small fibrils) on the properties of SNpc DNs. The introduction of α-syn aggregates into single DNs via the patch electrode significantly reduced both the input resistance and the firing rate without changing the membrane potential. These effects occurred after 8-16 min of dialysis but did not occur with the monomeric form of α-syn. The effects of α-syn aggregates could be significantly reduced by preincubation with the ATP-sensitive K+ channel (KATP) inhibitor glibenclamide. These data suggest that accumulation of α-syn aggregates in DNs may chronically activate KATP channels leading to a significant loss of excitability and dopamine release.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Alpha-Synuclein
/
Dopaminergic Neurons
Language:
En
Journal:
ENeuro
Year:
2021
Document type:
Article