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Alpha-synuclein aggregates increase the conductance of substantia nigra dopamine neurons, an effect partly reversed by the KATP channel inhibitor glibenclamide

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Hill, Emily, Gowers, Robert, Richardson, Magnus J. E. and Wall, Mark J. (2020) Alpha-synuclein aggregates increase the conductance of substantia nigra dopamine neurons, an effect partly reversed by the KATP channel inhibitor glibenclamide. eNeuro . ENEURO.0330-20.2020. doi:10.1523/ENEURO.0330-20.2020

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Official URL: http://doi.org/10.1523/ENEURO.0330-20.2020

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Abstract

Dopaminergic neurons in the substantia nigra pars compacta (SNpc) form an important part of the basal ganglia circuitry, playing key roles in movement initiation and co-ordination. A hallmark of Parkinson’s disease (PD) is the degeneration of these SNpc dopaminergic neurons leading to akinesia, bradykinesia and tremor. There is gathering evidence that oligomeric alpha synuclein (α-syn) is one of the major pathological species in PD, with its deposition in Lewy bodies closely correlated with disease progression. However the precise mechanisms underlying the effects of oligomeric α-syn on dopaminergic neuron function have yet to be fully defined. Here we have combined electrophysiological recording and detailed analysis to characterise the time-dependent effects of α-syn aggregates (consisting of oligomers and possibly small fibrils) on the properties of SNpc dopaminergic neurons. The introduction of α-syn aggregates into single dopaminergic neurons 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 minutes of dialysis but did not occur with the monomeric form of α-syn. The effects of α-syn aggregates could be significantly reduced by pre-incubation with the ATP-sensitive potassium channel (KATP) inhibitor glibenclamide. This data suggests that accumulation of α-syn aggregates in dopaminergic neurons may chronically activate KATP channels leading to a significant loss of excitability and dopamine release.

Item Type: Journal Article
Subjects: Q Science > QP Physiology
Divisions: Faculty of Science > Life Sciences (2010- )
Faculty of Science > Mathematics
Library of Congress Subject Headings (LCSH): Dopaminergic neurons, Alpha-synuclein, Nervous system -- Regeneration, Neurotrophic functions
Journal or Publication Title: eNeuro
Publisher: Society for Neuroscience
ISSN: 2373-2822
Official Date: 23 November 2020
Dates:
DateEvent
23 November 2020Published
18 October 2020Accepted
Date of first compliant deposit: 25 November 2020
Page Range: ENEURO.0330-20.2020
DOI: 10.1523/ENEURO.0330-20.2020
Status: Peer Reviewed
Publication Status: Published
Access rights to Published version: Restricted or Subscription Access
RIOXX Funder/Project Grant:
Project/Grant IDRIOXX Funder NameFunder ID
PhD Studentship[BBSRC] Biotechnology and Biological Sciences Research Councilhttp://dx.doi.org/10.13039/501100000268
PhD Studentship[EPSRC] Engineering and Physical Sciences Research Councilhttp://dx.doi.org/10.13039/501100000266

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