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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 ISSN 2373-2822.
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WRAP-Alpha-synuclein-aggregates-conductance-substantia-glibenclamide-Wall-2020.pdf - Published Version - Requires a PDF viewer. Available under License Creative Commons Attribution 4.0. Download (2728Kb) | Preview |
Official URL: http://doi.org/10.1523/ENEURO.0330-20.2020
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 | |||||||||
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| Subjects: | Q Science > QP Physiology | |||||||||
| Divisions: | Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) Faculty of Science, Engineering and Medicine > Science > Mathematics |
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| 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: |
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| 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 | |||||||||
| Date of first compliant deposit: | 25 November 2020 | |||||||||
| Date of first compliant Open Access: | 27 November 2020 | |||||||||
| RIOXX Funder/Project Grant: |
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